Datasets:

Haxirus

/

SLM_Pre-training_Dataset

like 0

Does Bupropion and Temazepam interact?

•Drug A: Bupropion •Drug B: Temazepam •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Temazepam is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Temazepam is specifically indicated only for the short-term management of insomnia,. Furthermore, such management is generally predominantly associated with the symptomatic relief of transient and short-term insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakenings. In particular, the official prescribing information for temazepam typically specifies that the instructions issued for dispensed prescriptions of the medication should indicate specifically that patients are only expected to use the therapy for short periods of time - usually 7-10 days in general. Subsequently, treatment with temazepam should usually not exceed 7 to 10 consecutive days and nor should it be prescribed in quantities exceeding a one-month supply. Some regional prescribing information also notes that temazepam may be used for premedication prior to minor surgery or other related procedures. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Temazepam is a benzodiazepine used as a hypnotic agent in the management of insomnia. Temazepam produces CNS depression at limbic, thalamic, and hypothalamic levels of the CNS. Temazepam increases the affinity of the neurotransmitter gamma-aminobutyric acid (GABA) for GABA receptors by binding to benzodiazepine receptors. Results are sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and anxiolytic action. In sleep laboratory studies, the effect of temazepam was compared to placebo during a two week period. The studies demonstrated a linear dose-response improvement in total sleep time and sleep latency with substantial drug-placebo differences apparent for total sleep time and for sleep latency at higher doses of temazepam. Regardless, REM sleep was ultimately unchanged but slow wave sleep was decreased. Moreover, a transient syndrome, known as "rebound insomnia", wherein the symptoms that led to treatment with temazepam in the first place recur in an enhanced form, may happen on withdrawal of temazepam treatment. The possibility of this occurrence is in part why long term use of temazepam is not recommended due to worries over tolerance and dependence wherein patients' bodies become physiologically accustomed to the regular presence and pharmacological effect of higher and higher doses of the benzodiazepine used. The duration of hypnotic effect and the profile of unwanted adverse effects may be influenced by the distribution and elimination half-lives of the administered temazepam and any active metabolites that may be formed. When such half-lives are long, the drug or its metabolite(s) may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours. Conversely, if half-lives are short, the drug and metabolites would be cleared before the next dose is ingested, and carry-over effects related to sedation or CNS depression should be minimal or not present at all. However, during nightly use and for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop - which may also contribute to the possibility of 'rebound insomnia'. Consequently, if the drug has a very short elimination half-life, it is possible that a relative deficiency (for example, in relation to benzodiazepine GABA(a) receptor sites) may occur at some point in the interval between each night's use. This sequence of events may account for certain clinical findings reported happening after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics, including increased wakefulness during the last third of the night and the appearance of increased daytime anxiety. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Gamma-Aminobutyric acid (GABA) is considered the principal inhibitory neurotransmitter in the human body. When GABA binds to GABA(a) receptors found in neuron synapses, chloride ions are conducted across neuron cell membranes via an ion channel in the receptors. With enough chloride ions conducted, the local, associated neuron membrane potentials are hyperpolarized - making it more difficult or less likely for action potentials to fire, ultimately resulting in less excitation of the neurons. Subsequently, benzodiazepines like temazepam can bind to benzodiazepine receptors that are components of various varieties of GABA(a) receptors. This binding acts to enhance the effects of GABA by increasing GABA affinity for the GABA(a) receptor, which ultimately enhances GABA ligand binding at the receptors. This enhanced ligand binding of the inhibitory neurotransmitter GABA to the receptors increases the aforementioned chloride ion conduction (perhaps reportedly via an increase in the frequency of the chloride channel opening), resulting in a hyperpolarized cell membrane that prevents further excitation of the associated neuron cells. Combined with the notion that such benzodiazepine receptor associated GABA(a) receptors exist both peripherally and in the CNS, this activity consequently facilitates various effects like sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and anxiolytic action. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Studies demonstrate that between 90 to 100% of an orally administered temazepam dose is absorbed, making the medication very well absorbed. The oral administration of 15 to 45 mg temazepam resulted in rapid absorption with significant blood levels achieved in 30 minutes and peak levels at 2-3 hours. In particular, direct studies following the oral ingestion of 30 mg of temazepam revealed measurable plasma concentrations were obtained 10-20 minutes after dosing with peak plasma levels ranging between 666-982 ng/mL (with a mean of 865 ng/mL) presenting approximately 1.2-1.6 hours (with a mean of 1.5 hours) after the dosing. Finally, a dose-proportional relationship was established for the area under the plasma concentration/time curve over the 15 to 30 mg dose range. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution documented for temazepam is 1.3-1.5 L/kg body weight - and in particular, 43-68 L/kg for the unbound fraction. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): It has been recorded that about 96% of unchanged temazepam is bound to plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): First-pass metabolism of temazepam is minimal at approximately 5-8% of an administered dose. Nevertheless, temazepam is principally metabolized in the liver where most of the unchanged drug is directly conjugated to glucuronide and excreted in the urine. In particular, the primary metabolite present in the blood is the O-conjugate of temazepam. Less than 5% of the drug is demethylated to oxazepam and subsequently eliminated as the glucuronide. Regardless, the glucuronides of temazepam have no demonstrable CNS activity and it is believed that no active metabolites are formed in general. Since temazepam mainly undergoes Phase II conjugation reactions, it is proposed that it is devoid of CYP450 interactions. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following a single dose, 80-90% of the dose appears in the urine, predominantly as the O-conjugate metabolite, and 3-13% of the dose appears in the faeces. Less than 2% of the dose is excreted unchanged or as N-desmethyltemazepam in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The terminal half-life determined for temazepam is recorded as being between 3.5-18 hours, with a mean of 9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Studies regarding the clearance of temazepam have recorded the values of 1.03 ml/min/kg and 31 ml/min/kg for the clearance of total temazepam and the clearance of unbound temazepam, respectively. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Manifestations of acute overdosage of temazepam, as with other benzodiazepines, can be expected to reflect the increasing CNS effects of the drug and include somnolence, confusion, and coma, with reduced or absent reflexes. With large overdoses, respiratory depression, hypotension, and finally coma can occur. Benzodiazepines like temazepam might cause fetal harm when administered to a pregnant woman. Transplacental distribution has in the past resulted in neonatal CNS depression following the ingestion of therapeutic doses of related benzodiazepine hypnotics like diazepam during the last weeks of pregnancy. It is not known whether this drug is excreted in human milk. Caution should, therefore, be exercised when temazepam is administered to a nursing woman. Safety and effectiveness in pediatric patients have not been established. Lower doses of temazepam, like 7.5 mg is recommended as the initial dosage for patients aged 65 and over since the risk of the development of oversedation, dizziness, confusion, ataxia and/or falls increases substantially with larger doses of benzodiazepines in elderly and debilitated patients. No evidence of carcinogenicity was observed in animal studies although hyperplastic liver nodules were observed in female mice exposed to the highest doses of temazepam. The clinical significance of this finding is not known. Fertility in male and female rats was not adversely affected by temazepam toxicity studies. No mutagenicity tests have been done with temazepam. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Restoril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Temazepam is a short-acting benzodiazepine commonly used to treat panic disorders, severe anxiety, and insomnia.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Temazepam interact? Information: •Drug A: Bupropion •Drug B: Temazepam •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Temazepam is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Temazepam is specifically indicated only for the short-term management of insomnia,. Furthermore, such management is generally predominantly associated with the symptomatic relief of transient and short-term insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakenings. In particular, the official prescribing information for temazepam typically specifies that the instructions issued for dispensed prescriptions of the medication should indicate specifically that patients are only expected to use the therapy for short periods of time - usually 7-10 days in general. Subsequently, treatment with temazepam should usually not exceed 7 to 10 consecutive days and nor should it be prescribed in quantities exceeding a one-month supply. Some regional prescribing information also notes that temazepam may be used for premedication prior to minor surgery or other related procedures. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Temazepam is a benzodiazepine used as a hypnotic agent in the management of insomnia. Temazepam produces CNS depression at limbic, thalamic, and hypothalamic levels of the CNS. Temazepam increases the affinity of the neurotransmitter gamma-aminobutyric acid (GABA) for GABA receptors by binding to benzodiazepine receptors. Results are sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and anxiolytic action. In sleep laboratory studies, the effect of temazepam was compared to placebo during a two week period. The studies demonstrated a linear dose-response improvement in total sleep time and sleep latency with substantial drug-placebo differences apparent for total sleep time and for sleep latency at higher doses of temazepam. Regardless, REM sleep was ultimately unchanged but slow wave sleep was decreased. Moreover, a transient syndrome, known as "rebound insomnia", wherein the symptoms that led to treatment with temazepam in the first place recur in an enhanced form, may happen on withdrawal of temazepam treatment. The possibility of this occurrence is in part why long term use of temazepam is not recommended due to worries over tolerance and dependence wherein patients' bodies become physiologically accustomed to the regular presence and pharmacological effect of higher and higher doses of the benzodiazepine used. The duration of hypnotic effect and the profile of unwanted adverse effects may be influenced by the distribution and elimination half-lives of the administered temazepam and any active metabolites that may be formed. When such half-lives are long, the drug or its metabolite(s) may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours. Conversely, if half-lives are short, the drug and metabolites would be cleared before the next dose is ingested, and carry-over effects related to sedation or CNS depression should be minimal or not present at all. However, during nightly use and for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop - which may also contribute to the possibility of 'rebound insomnia'. Consequently, if the drug has a very short elimination half-life, it is possible that a relative deficiency (for example, in relation to benzodiazepine GABA(a) receptor sites) may occur at some point in the interval between each night's use. This sequence of events may account for certain clinical findings reported happening after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics, including increased wakefulness during the last third of the night and the appearance of increased daytime anxiety. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Gamma-Aminobutyric acid (GABA) is considered the principal inhibitory neurotransmitter in the human body. When GABA binds to GABA(a) receptors found in neuron synapses, chloride ions are conducted across neuron cell membranes via an ion channel in the receptors. With enough chloride ions conducted, the local, associated neuron membrane potentials are hyperpolarized - making it more difficult or less likely for action potentials to fire, ultimately resulting in less excitation of the neurons. Subsequently, benzodiazepines like temazepam can bind to benzodiazepine receptors that are components of various varieties of GABA(a) receptors. This binding acts to enhance the effects of GABA by increasing GABA affinity for the GABA(a) receptor, which ultimately enhances GABA ligand binding at the receptors. This enhanced ligand binding of the inhibitory neurotransmitter GABA to the receptors increases the aforementioned chloride ion conduction (perhaps reportedly via an increase in the frequency of the chloride channel opening), resulting in a hyperpolarized cell membrane that prevents further excitation of the associated neuron cells. Combined with the notion that such benzodiazepine receptor associated GABA(a) receptors exist both peripherally and in the CNS, this activity consequently facilitates various effects like sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and anxiolytic action. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Studies demonstrate that between 90 to 100% of an orally administered temazepam dose is absorbed, making the medication very well absorbed. The oral administration of 15 to 45 mg temazepam resulted in rapid absorption with significant blood levels achieved in 30 minutes and peak levels at 2-3 hours. In particular, direct studies following the oral ingestion of 30 mg of temazepam revealed measurable plasma concentrations were obtained 10-20 minutes after dosing with peak plasma levels ranging between 666-982 ng/mL (with a mean of 865 ng/mL) presenting approximately 1.2-1.6 hours (with a mean of 1.5 hours) after the dosing. Finally, a dose-proportional relationship was established for the area under the plasma concentration/time curve over the 15 to 30 mg dose range. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution documented for temazepam is 1.3-1.5 L/kg body weight - and in particular, 43-68 L/kg for the unbound fraction. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): It has been recorded that about 96% of unchanged temazepam is bound to plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): First-pass metabolism of temazepam is minimal at approximately 5-8% of an administered dose. Nevertheless, temazepam is principally metabolized in the liver where most of the unchanged drug is directly conjugated to glucuronide and excreted in the urine. In particular, the primary metabolite present in the blood is the O-conjugate of temazepam. Less than 5% of the drug is demethylated to oxazepam and subsequently eliminated as the glucuronide. Regardless, the glucuronides of temazepam have no demonstrable CNS activity and it is believed that no active metabolites are formed in general. Since temazepam mainly undergoes Phase II conjugation reactions, it is proposed that it is devoid of CYP450 interactions. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following a single dose, 80-90% of the dose appears in the urine, predominantly as the O-conjugate metabolite, and 3-13% of the dose appears in the faeces. Less than 2% of the dose is excreted unchanged or as N-desmethyltemazepam in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The terminal half-life determined for temazepam is recorded as being between 3.5-18 hours, with a mean of 9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Studies regarding the clearance of temazepam have recorded the values of 1.03 ml/min/kg and 31 ml/min/kg for the clearance of total temazepam and the clearance of unbound temazepam, respectively. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Manifestations of acute overdosage of temazepam, as with other benzodiazepines, can be expected to reflect the increasing CNS effects of the drug and include somnolence, confusion, and coma, with reduced or absent reflexes. With large overdoses, respiratory depression, hypotension, and finally coma can occur. Benzodiazepines like temazepam might cause fetal harm when administered to a pregnant woman. Transplacental distribution has in the past resulted in neonatal CNS depression following the ingestion of therapeutic doses of related benzodiazepine hypnotics like diazepam during the last weeks of pregnancy. It is not known whether this drug is excreted in human milk. Caution should, therefore, be exercised when temazepam is administered to a nursing woman. Safety and effectiveness in pediatric patients have not been established. Lower doses of temazepam, like 7.5 mg is recommended as the initial dosage for patients aged 65 and over since the risk of the development of oversedation, dizziness, confusion, ataxia and/or falls increases substantially with larger doses of benzodiazepines in elderly and debilitated patients. No evidence of carcinogenicity was observed in animal studies although hyperplastic liver nodules were observed in female mice exposed to the highest doses of temazepam. The clinical significance of this finding is not known. Fertility in male and female rats was not adversely affected by temazepam toxicity studies. No mutagenicity tests have been done with temazepam. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Restoril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Temazepam is a short-acting benzodiazepine commonly used to treat panic disorders, severe anxiety, and insomnia. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Temozolomide interact?

•Drug A: Bupropion •Drug B: Temozolomide •Severity: MINOR •Description: Temozolomide may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Temozolomide is indicated in adult patients for the treatment of newly diagnosed glioblastoma concomitantly with radiotherapy and for use as maintenance treatment thereafter. It is also indicated for the treatment of refractory anaplastic astrocytoma in adult patients or adjuvant therapy for adults with newly diagnosed anaplastic astrocytoma. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH in vivo to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death. Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients. Patients must have an ANC of ≥1.5 x 10 /L and a platelet count of ≥100 x 10 /L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and 22 of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages. Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose. Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, respectively. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Glioblastoma (glioblastoma multiforme) is the most common and aggressive adult primary brain tumour, accounting for 45.6% of all primary malignant brain tumours. Primarily defined histopathologically by necrosis and microvascular proliferation (WHO grade IV classification), glioblastomas are commonly treated through radiotherapy and concomitant alkylation-based chemotherapy with temozolomide. Temozolomide (TMZ) is a small (194 Da) lipophilic alkylating agent of the imidazotetrazine class that is stable at acidic pH, allowing for both oral and intravenous dosing, and can cross the blood-brain barrier to affect CNS tumours. After absorption, TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. Brain tumours such as glioblastoma typically possess a more alkaline pH than healthy tissue, favouring TMZ activation within tumour tissue. The methyl diazonium cation is highly reactive and methylates DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). Although more prevalent, N7-MeG and N3-MeA are rapidly repaired by the base excision repair pathway and are not primary mediators of temozolomide toxicity, although N3-MeA lesions are lethal if not repaired. By comparison, repair of O6-MeG requires action by the suicide enzyme methylguanine-DNA methyltransferase (MGMT), which removes the methyl group to restore guanine. If not repaired by MGMT, O6-MeG mispairs with thymine, activating the DNA mismatch repair (MMR) pathway that removes the thymine (not the O6-MeG), resulting in futile cycles of repair and eventual DNA strand breaks leading to apoptosis. As MMR activity is crucial for temozolomide cytotoxicity, cells that have reduced or absent MGMT function and an intact MMR pathway are the most sensitive to temozolomide treatment. Glioblastomas that upregulate MGMT downregulate MMR or alter both are resistant to TMZ, leading to treatment failure. More recently, increased interest has also been shown in the immunomodulatory effects of TMZ, related to its myelosuppressive effects. Counterintuitively, lymphodepletion may enhance the antitumour effects of cellular immunotherapy and improve the dynamics of memory cells by altering tumour-specific versus tumour-tolerant populations. The depletion of tumour-localized immunosuppressive T reg cells may contribute to an improved response to immunotherapy. Hence, TMZ treatment may also form the backbone of immunotherapy strategies against glioblastoma in the future. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Temozolomide is rapidly and completely absorbed in the gastrointestinal tract and is stable at both acidic and neutral pH. Therefore, temozolomide may be administered both orally and intravenously with a median T max of one hour. Following a single oral dose of 150 mg/m, temozolomide and its active MTIC metabolite had C max values of 7.5 μg/mL and 282 ng/mL and AUC values of 23.4 μg*hr/mL and 864 ng*hr/mL, respectively. Similarly, following a single 90-minute IV infusion of 150 mg/m, temozolide and its active MTIC metabolite had C max values of 7.3 μg/mL and 276 ng/mL and AUC values of 24.6 μg*hr/mL and 891 ng*hr/mL, respectively. Temozolomide kinetics are linear over the range of 75-250 mg/m /day. The median T max is 1 hour Oral temozolomide absorption is affected by food. Administration following a high-fat breakfast of 587 calories caused the mean C max and AUC to decrease by 32% and 9%, respectively, and the median T max to increase by 2-fold (from 1-2.25 hours). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Temozolomide has a mean apparent volume of distribution (%CV) of 0.4 (13%) L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Temozolomide plasma protein binding varies from 8-36%, with an average of around 15%. In vitro binding experiments revealed approximate dissociation constants of 0.2-0.25 and 0.12 mM for temozolomide with human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), respectively; despite the slightly higher affinity for AGP, it is likely that temozolomide is predominantly bound to HSA due to its higher serum concentration. In addition, temozolomide binding to HSA results in delayed hydrolysis and a longer half-life than in buffer (1 versus 1.8 hours). •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): After absorption, temozolomide undergoes nonenzymatic chemical conversion to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) plus carbon dioxide and to a temozolomide acid metabolite, which occurs at physiological pH but is enhanced with increasing alkalinity. MTIC subsequently reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation, the active alkylating species. The cytochrome P450 system plays only a minor role in temozolomide metabolism. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Roughly 38% of administered temozolomide can be recovered over seven days, with 38% in the urine and only 0.8% in the feces. The recovered material comprises mainly metabolites: unidentified polar metabolites (17%), AIC (12%), and the temozolomide acid metabolite (2.3%). Only 6% of the recovered dose represents unchanged temozolomide. •Half-life (Drug A): 24 hours •Half-life (Drug B): Temozolomide has a mean elimination half-life of 1.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Temozolomide has a clearance of approximately 5.5 L/hr/m. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The primary dose-limiting toxicity of temozolomide is myelosuppression, which can occur with any dose but is more severe at higher doses. Patients taking high doses experienced adverse reactions, including severe and prolonged myelosuppression, infections, and death. One patient who took 2000 mg/day for five days experienced pancytopenia, pyrexia, and multi-organ failure, which resulted in death. Patients experiencing an overdose should have complete blood counts monitored and provided with supportive care as necessary. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Temodar, Temomedac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-perillyl alcohol temozolomide Methazolastone Temozolodida Temozolomid Temozolomida Témozolomide Temozolomide Temozolomidum TMZ •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Temozolomide is an alkylating agent used to treat glioblastoma multiforme and refractory anaplastic astrocytoma.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Temozolomide interact? Information: •Drug A: Bupropion •Drug B: Temozolomide •Severity: MINOR •Description: Temozolomide may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Temozolomide is indicated in adult patients for the treatment of newly diagnosed glioblastoma concomitantly with radiotherapy and for use as maintenance treatment thereafter. It is also indicated for the treatment of refractory anaplastic astrocytoma in adult patients or adjuvant therapy for adults with newly diagnosed anaplastic astrocytoma. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH in vivo to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death. Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients. Patients must have an ANC of ≥1.5 x 10 /L and a platelet count of ≥100 x 10 /L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and 22 of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages. Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose. Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, respectively. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Glioblastoma (glioblastoma multiforme) is the most common and aggressive adult primary brain tumour, accounting for 45.6% of all primary malignant brain tumours. Primarily defined histopathologically by necrosis and microvascular proliferation (WHO grade IV classification), glioblastomas are commonly treated through radiotherapy and concomitant alkylation-based chemotherapy with temozolomide. Temozolomide (TMZ) is a small (194 Da) lipophilic alkylating agent of the imidazotetrazine class that is stable at acidic pH, allowing for both oral and intravenous dosing, and can cross the blood-brain barrier to affect CNS tumours. After absorption, TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. Brain tumours such as glioblastoma typically possess a more alkaline pH than healthy tissue, favouring TMZ activation within tumour tissue. The methyl diazonium cation is highly reactive and methylates DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). Although more prevalent, N7-MeG and N3-MeA are rapidly repaired by the base excision repair pathway and are not primary mediators of temozolomide toxicity, although N3-MeA lesions are lethal if not repaired. By comparison, repair of O6-MeG requires action by the suicide enzyme methylguanine-DNA methyltransferase (MGMT), which removes the methyl group to restore guanine. If not repaired by MGMT, O6-MeG mispairs with thymine, activating the DNA mismatch repair (MMR) pathway that removes the thymine (not the O6-MeG), resulting in futile cycles of repair and eventual DNA strand breaks leading to apoptosis. As MMR activity is crucial for temozolomide cytotoxicity, cells that have reduced or absent MGMT function and an intact MMR pathway are the most sensitive to temozolomide treatment. Glioblastomas that upregulate MGMT downregulate MMR or alter both are resistant to TMZ, leading to treatment failure. More recently, increased interest has also been shown in the immunomodulatory effects of TMZ, related to its myelosuppressive effects. Counterintuitively, lymphodepletion may enhance the antitumour effects of cellular immunotherapy and improve the dynamics of memory cells by altering tumour-specific versus tumour-tolerant populations. The depletion of tumour-localized immunosuppressive T reg cells may contribute to an improved response to immunotherapy. Hence, TMZ treatment may also form the backbone of immunotherapy strategies against glioblastoma in the future. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Temozolomide is rapidly and completely absorbed in the gastrointestinal tract and is stable at both acidic and neutral pH. Therefore, temozolomide may be administered both orally and intravenously with a median T max of one hour. Following a single oral dose of 150 mg/m, temozolomide and its active MTIC metabolite had C max values of 7.5 μg/mL and 282 ng/mL and AUC values of 23.4 μg*hr/mL and 864 ng*hr/mL, respectively. Similarly, following a single 90-minute IV infusion of 150 mg/m, temozolide and its active MTIC metabolite had C max values of 7.3 μg/mL and 276 ng/mL and AUC values of 24.6 μg*hr/mL and 891 ng*hr/mL, respectively. Temozolomide kinetics are linear over the range of 75-250 mg/m /day. The median T max is 1 hour Oral temozolomide absorption is affected by food. Administration following a high-fat breakfast of 587 calories caused the mean C max and AUC to decrease by 32% and 9%, respectively, and the median T max to increase by 2-fold (from 1-2.25 hours). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Temozolomide has a mean apparent volume of distribution (%CV) of 0.4 (13%) L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Temozolomide plasma protein binding varies from 8-36%, with an average of around 15%. In vitro binding experiments revealed approximate dissociation constants of 0.2-0.25 and 0.12 mM for temozolomide with human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), respectively; despite the slightly higher affinity for AGP, it is likely that temozolomide is predominantly bound to HSA due to its higher serum concentration. In addition, temozolomide binding to HSA results in delayed hydrolysis and a longer half-life than in buffer (1 versus 1.8 hours). •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): After absorption, temozolomide undergoes nonenzymatic chemical conversion to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) plus carbon dioxide and to a temozolomide acid metabolite, which occurs at physiological pH but is enhanced with increasing alkalinity. MTIC subsequently reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation, the active alkylating species. The cytochrome P450 system plays only a minor role in temozolomide metabolism. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Roughly 38% of administered temozolomide can be recovered over seven days, with 38% in the urine and only 0.8% in the feces. The recovered material comprises mainly metabolites: unidentified polar metabolites (17%), AIC (12%), and the temozolomide acid metabolite (2.3%). Only 6% of the recovered dose represents unchanged temozolomide. •Half-life (Drug A): 24 hours •Half-life (Drug B): Temozolomide has a mean elimination half-life of 1.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Temozolomide has a clearance of approximately 5.5 L/hr/m. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The primary dose-limiting toxicity of temozolomide is myelosuppression, which can occur with any dose but is more severe at higher doses. Patients taking high doses experienced adverse reactions, including severe and prolonged myelosuppression, infections, and death. One patient who took 2000 mg/day for five days experienced pancytopenia, pyrexia, and multi-organ failure, which resulted in death. Patients experiencing an overdose should have complete blood counts monitored and provided with supportive care as necessary. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Temodar, Temomedac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-perillyl alcohol temozolomide Methazolastone Temozolodida Temozolomid Temozolomida Témozolomide Temozolomide Temozolomidum TMZ •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Temozolomide is an alkylating agent used to treat glioblastoma multiforme and refractory anaplastic astrocytoma. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Teniposide interact?

•Drug A: Bupropion •Drug B: Teniposide •Severity: MODERATE •Description: The metabolism of Bupropion can be decreased when combined with Teniposide. •Extended Description: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Teniposide is used for the treatment of refractory acute lymphoblastic leukaemia •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G 2 phase of the cell cycle. Teniposide prevents cell mitosis by causing single and double stranded DNA breaks as well as cross linking between protein and DNA. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. Teniposide binds to and inhibits DNA topoisomerase II. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): 5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 10.3 mL/min/m2 •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Epidophyllotoxin Teniposid Téniposide Teniposide Teniposido Teniposidum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Teniposide is a cytotoxic drug used as an adjunct for chemotherapy induction in the treatment of refractory childhood acute lymphoblastic leukemia.

The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is moderate.

Question: Does Bupropion and Teniposide interact? Information: •Drug A: Bupropion •Drug B: Teniposide •Severity: MODERATE •Description: The metabolism of Bupropion can be decreased when combined with Teniposide. •Extended Description: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Teniposide is used for the treatment of refractory acute lymphoblastic leukaemia •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G 2 phase of the cell cycle. Teniposide prevents cell mitosis by causing single and double stranded DNA breaks as well as cross linking between protein and DNA. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. Teniposide binds to and inhibits DNA topoisomerase II. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): 5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 10.3 mL/min/m2 •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Epidophyllotoxin Teniposid Téniposide Teniposide Teniposido Teniposidum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Teniposide is a cytotoxic drug used as an adjunct for chemotherapy induction in the treatment of refractory childhood acute lymphoblastic leukemia. Output: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is moderate.

Does Bupropion and Tenofovir alafenamide interact?

•Drug A: Bupropion •Drug B: Tenofovir alafenamide •Severity: MODERATE •Description: The serum concentration of Tenofovir alafenamide can be increased when it is combined with Bupropion. •Extended Description: Because tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs and this may increase the risk of adverse reactions. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tenofovir alafenamide is indicated for the treatment of hepatitis B virus infection in adults and pediatric patients 12 years of age and older with compensated liver disease. In combination with emtricitabine and other antiretrovirals, it is indicated for the treatment of HIV-1 infection in adolescent and adult patients with a weight higher than 35 kg. This combination is also indicated to prevent HIV-1 infections in high risk adolescent and adult patients, excluding patients at risk from receptive vaginal sex. When combined with antiretrovirals other than protease inhibitors that require a CYP3A inhibitor, it can be used to treat pediatric patients weighing 25-35 kg. In the combination product with emtricitabine and bictegravir, tenofovir alafenamide is considered a complete treatment regimen for HIV-1 infections for treatment-naive patients or patients virologically suppressed for at least three months with no history of treatment failure. Additionally, the combination product including elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide and the combination product including emtricitabine, rilpivirine and tenofovir alafenamide can be used in the treatment of HIV-1 infection in patients older than 12 years with no previous antiretroviral therapy history or who are virologically suppressed for at least 6 months with no history of treatment failure. The combination product including darunavir, cobicistat, emtricitabine, and tenofovir alafenamide is indicated for the treatment of HIV-1 infection in adults without prior antiretroviral therapy or in patients virologically suppressed for 6 months and no reported resistance to darunavir or tenofovir. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tenofovir alafenamide has been shown to be a potent inhibitor of hepatitis B viral replication. Tenofovir alafenamide presents a better renal tolerance when compared with the counterpart tenofovir disoproxil. This improved safety profile seems to be related to a lower plasma concentration of tenofovir. In clinical trials, tenofovir alafenamide was shown to present 5-fold more potent antiviral activity against HIV-1 when compared to tenofovir disoproxil. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tenofovir alafenamide presents 91% lower plasma concentration with an intracellular presence of about 20-fold higher when compared to tenofovir disoproxil. This is due to its prolonged systemic exposure and its higher intracellular accumulation of the active metabolite tenofovir diphosphate. Tenofovir alafenamide accumulates more in peripheral blood mononuclear cells compared to red blood cells. Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase, causing chain termination and the inhibition of viral synthesis. To know more about the specific mechanism of action of the active form, please visit the drug entry of tenofovir. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): As compared to the parent molecule, tenofovir, tenofovir alafenamide presents a lipophilic group that masks the negative charge of the parent moiety which improves its oral bioavailability. Tenofovir alafenamide is highly stable in plasma and, after administration of this prodrug, there is a low concentration of tenofovir in plasma. After oral administration, tenofovir alafenamide is rapidly absorbed by the gut. When a single dose is administered, a peak concentration of 16 ng/ml of the parent compound, corresponding to about 73% of the dose, is observed after 2 hours with an AUC of 270 ng*h/mL. Once inside the body, tenofovir alafenamide enters hepatocytes by passive diffusion regulated by the organic anion transporters 1B1 and 1B3 for its activation. Administration of tenofovir alafenamide concomitantly with a high-fat meal results in an increase of about 65% in its internal exposure. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In clinical trials, the reported volume of distribution of tenofovir alafenamide was higher than 100 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tenofovir alafenamide is reported to bind to plasma proteins and ex vivo studies have registered that approximately 80% of the administered dose of this drug is presented in a bound state. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): To be activated, tenofovir alafenamide is required to be hydrolyzed to the parent compound tenofovir by the activity of cathepsin A or carboxylesterase 1. Tenofovir alafenamide presents significant plasma stability and hence, its activation is performed inside the target cells. After activation, tenofovir is further processed and after 1-2 days, it is detected in plasma almost completely transformed to uric acid. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tenofovir alafenamide has been registered to present a bile elimination that corresponds to 47% of the administered dose and a renal elimination the represents about 36%. From the recovered dose in urine, about 75% is represented as unchanged tenofovir followed by uric acid and a small dose of tenofovir alafenamide. On the other hand, in feces, 99% of the recovered dose corresponds to tenofovir. •Half-life (Drug A): 24 hours •Half-life (Drug B): The reported half-life for tenofovir alafenamide is of 0.51 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The reported clearance rate of tenofovir alafenamide is 117 L/h. In patients with severe renal impairment, this value can be decreased by 50%, reporting a rate of 61.7 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The LD 50 of tenofovir alafenamide has not been reported. In cases of overdose, continuous monitoring of vital signs is required as the adverse effects in high doses has not been evaluated. However, in case of overdose, tenofovir is efficiently removed by hemodialysis with an extraction coefficient of 54%. Carcinogenic reports have only been performed with tenofovir disoproxil and it is important to consider that tenofovir alafenamide does not present a high systemic exposure. However, long-term exposure with 10-fold dosages of tenofovir disoproxil was reported to produce liver adenomas in females. Tenofovir alafenamide was not reported to present mutagenic potential and it did not present effects on fertility. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Biktarvy, Descovy, Genvoya, Odefsey, Vemlidy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tenofovir alafenamide is a nucleoside analog reverse transcriptase inhibitor used for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease.

Because tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs and this may increase the risk of adverse reactions. The severity of the interaction is moderate.

Question: Does Bupropion and Tenofovir alafenamide interact? Information: •Drug A: Bupropion •Drug B: Tenofovir alafenamide •Severity: MODERATE •Description: The serum concentration of Tenofovir alafenamide can be increased when it is combined with Bupropion. •Extended Description: Because tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs and this may increase the risk of adverse reactions. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tenofovir alafenamide is indicated for the treatment of hepatitis B virus infection in adults and pediatric patients 12 years of age and older with compensated liver disease. In combination with emtricitabine and other antiretrovirals, it is indicated for the treatment of HIV-1 infection in adolescent and adult patients with a weight higher than 35 kg. This combination is also indicated to prevent HIV-1 infections in high risk adolescent and adult patients, excluding patients at risk from receptive vaginal sex. When combined with antiretrovirals other than protease inhibitors that require a CYP3A inhibitor, it can be used to treat pediatric patients weighing 25-35 kg. In the combination product with emtricitabine and bictegravir, tenofovir alafenamide is considered a complete treatment regimen for HIV-1 infections for treatment-naive patients or patients virologically suppressed for at least three months with no history of treatment failure. Additionally, the combination product including elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide and the combination product including emtricitabine, rilpivirine and tenofovir alafenamide can be used in the treatment of HIV-1 infection in patients older than 12 years with no previous antiretroviral therapy history or who are virologically suppressed for at least 6 months with no history of treatment failure. The combination product including darunavir, cobicistat, emtricitabine, and tenofovir alafenamide is indicated for the treatment of HIV-1 infection in adults without prior antiretroviral therapy or in patients virologically suppressed for 6 months and no reported resistance to darunavir or tenofovir. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tenofovir alafenamide has been shown to be a potent inhibitor of hepatitis B viral replication. Tenofovir alafenamide presents a better renal tolerance when compared with the counterpart tenofovir disoproxil. This improved safety profile seems to be related to a lower plasma concentration of tenofovir. In clinical trials, tenofovir alafenamide was shown to present 5-fold more potent antiviral activity against HIV-1 when compared to tenofovir disoproxil. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tenofovir alafenamide presents 91% lower plasma concentration with an intracellular presence of about 20-fold higher when compared to tenofovir disoproxil. This is due to its prolonged systemic exposure and its higher intracellular accumulation of the active metabolite tenofovir diphosphate. Tenofovir alafenamide accumulates more in peripheral blood mononuclear cells compared to red blood cells. Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase, causing chain termination and the inhibition of viral synthesis. To know more about the specific mechanism of action of the active form, please visit the drug entry of tenofovir. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): As compared to the parent molecule, tenofovir, tenofovir alafenamide presents a lipophilic group that masks the negative charge of the parent moiety which improves its oral bioavailability. Tenofovir alafenamide is highly stable in plasma and, after administration of this prodrug, there is a low concentration of tenofovir in plasma. After oral administration, tenofovir alafenamide is rapidly absorbed by the gut. When a single dose is administered, a peak concentration of 16 ng/ml of the parent compound, corresponding to about 73% of the dose, is observed after 2 hours with an AUC of 270 ng*h/mL. Once inside the body, tenofovir alafenamide enters hepatocytes by passive diffusion regulated by the organic anion transporters 1B1 and 1B3 for its activation. Administration of tenofovir alafenamide concomitantly with a high-fat meal results in an increase of about 65% in its internal exposure. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In clinical trials, the reported volume of distribution of tenofovir alafenamide was higher than 100 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tenofovir alafenamide is reported to bind to plasma proteins and ex vivo studies have registered that approximately 80% of the administered dose of this drug is presented in a bound state. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): To be activated, tenofovir alafenamide is required to be hydrolyzed to the parent compound tenofovir by the activity of cathepsin A or carboxylesterase 1. Tenofovir alafenamide presents significant plasma stability and hence, its activation is performed inside the target cells. After activation, tenofovir is further processed and after 1-2 days, it is detected in plasma almost completely transformed to uric acid. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tenofovir alafenamide has been registered to present a bile elimination that corresponds to 47% of the administered dose and a renal elimination the represents about 36%. From the recovered dose in urine, about 75% is represented as unchanged tenofovir followed by uric acid and a small dose of tenofovir alafenamide. On the other hand, in feces, 99% of the recovered dose corresponds to tenofovir. •Half-life (Drug A): 24 hours •Half-life (Drug B): The reported half-life for tenofovir alafenamide is of 0.51 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The reported clearance rate of tenofovir alafenamide is 117 L/h. In patients with severe renal impairment, this value can be decreased by 50%, reporting a rate of 61.7 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The LD 50 of tenofovir alafenamide has not been reported. In cases of overdose, continuous monitoring of vital signs is required as the adverse effects in high doses has not been evaluated. However, in case of overdose, tenofovir is efficiently removed by hemodialysis with an extraction coefficient of 54%. Carcinogenic reports have only been performed with tenofovir disoproxil and it is important to consider that tenofovir alafenamide does not present a high systemic exposure. However, long-term exposure with 10-fold dosages of tenofovir disoproxil was reported to produce liver adenomas in females. Tenofovir alafenamide was not reported to present mutagenic potential and it did not present effects on fertility. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Biktarvy, Descovy, Genvoya, Odefsey, Vemlidy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tenofovir alafenamide is a nucleoside analog reverse transcriptase inhibitor used for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease. Output: Because tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs and this may increase the risk of adverse reactions. The severity of the interaction is moderate.

Does Bupropion and Tenofovir disoproxil interact?

•Drug A: Bupropion •Drug B: Tenofovir disoproxil •Severity: MINOR •Description: Tenofovir disoproxil may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tenofovir disoproxil is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in patients ≥2 years old and weighing ≥10 kg. It is also indicated for the treatment of chronic hepatitis B in patients ≥2 years old and weighing ≥10 kg. Tenofovir disoproxil is also an ingredient in several combination products, all of which are indicated either alone or in combination with other antiretrovirals for the treatment of HIV-1 infection. In addition, tenofovir disoproxil is available in combination with emtricitabine (under the brand name Truvada) for use as pre-exposure prophylaxis (PrEP) in at-risk adults and adolescents weighing ≥ 35kg to reduce the risk of sexually-acquired HIV-1 infection. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): This drug prevents viral DNA chain elongation through inhibition of enzymes necessary for host cell infection viral replication in HIV-1 and Hepatitis B infections,. In vitro effects The antiviral activity of tenofovir against in laboratory and clinical isolates of HIV-1 was studied in lymphoblastoid cell lines, primary monocyte/macrophage cells, in addition to peripheral blood lymphocytes. The EC50 (50% effective concentration) values of tenofovir against HIV-1 virus ranged between 0.04 μM to 8.5 μM. Combination of tenofovir disoproxil with other drugs In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive and synergistic effects were seen. Tenofovir demonstrated antiviral activities in cell cultures against HIV-1. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tenofovir belongs to a class of antiretroviral drugs known as nucleotide analog reverse transcriptase inhibitors (NtRTIs), which block reverse transcriptase, an enzyme necessary for viral production in HIV-infected individuals. This enables the management of HIV viral load through decreased viral replication. Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to its active form, tenofovir, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, a chain terminator, by constitutively expressed enzymes in the cell. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the Hepatitis B polymerase by direct binding competition with the natural deoxyribonucleotide substrate (deoxyadenosine 5’-triphosphate) and, after integration into DNA, causes viral DNA chain termination,. A note on resistance HIV-1 isolates with decreased susceptibility to tenofovir have been identified in cell culture studies. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2– 4 fold decrease in susceptibility to treatment with tenofovir. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After oral administration of tenofovir disoproxil to patients with HIV infection, tenofovir disoproxil is quickly absorbed and metabolized to tenofovir. Administration of tenofovir disoproxil 300 mg tablets after a high-fat meal increases the oral bioavailability of this drug, as demonstrated by an increase in tenofovir AUC0-∞ of about 40% as well as an increase in Cmax of about 14%. On the contrary, the administration of tenofovir disoproxil with a light meal did not exert a relevant effect on the pharmacokinetics of tenofovir when compared to administration under fasting conditions. The presence of ingested food slows the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL after several doses of tenofovir disoproxil 300 mg once daily in the fed state when meal content is not controlled. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg. After oral administration of tenofovir disoproxil, tenofovir is distributed to the majority tissues with the highest concentrations measured in the kidney, liver and the intestinal contents (based on data from preclinical studies). •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): In vitro binding of tenofovir to human plasma or serum proteins is <0.7 and <7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to its active form, tenofovir, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, a chain terminator, by constitutively expressed enzymes in the cell. Two phosphorylation steps are required to convert tenofovir disoproxil to the active drug form. The cytochrome P450 enzyme system is not involved with the metabolism of tenofovir disoproxil or tenofovir. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also eliminated by the kidneys. •Half-life (Drug A): 24 hours •Half-life (Drug B): When a single oral dose is given, the terminal elimination half-life is approximately 17 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of tenofovir is highly dependent on renal function and may vary greatly. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min). On average, renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 210 ml/min), which is in excess of the glomerular filtration rate. This shows that active tubular secretion is an essential part of the elimination of tenofovir. The FDA label provides specific guidelines for dosing according to renal function. It is important to consult product labeling before administering tenofovir to individuals with renal dysfunction, as the clearance of this drug may vary greatly among these patients. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): A note on breastfeeding The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to prevent postnatal transmission of HIV-1. Mothers should be advised not to breast-feed if they are receiving tenofovir disoproxil. Carcinogenesis Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were performed at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the higher dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose. Pregnancy This drug is considered a pregnancy Category B drug. Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the recommended human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not consistently reflective of human effects, tenofovir disoproxil should be used during pregnancy only if clearly required. To monitor fetal outcomes of pregnant women taking tenofovir disoproxil, an Antiretroviral Pregnancy Registry has been formed. Healthcare providers are encouraged and advised to register patients by calling the number listed on the FDA label for tenofovir disoproxil. Mutagenesis Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative for mutagenesis in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice. Impairment of Fertility There were no observed effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was given to male rats at a dose comparable to 10 times the human dose based on body surface area comparisons for 28 days before mating and to female rats for 15 days before mating through day seven of gestation. There was, however, changes in the estrous cycle in female rats. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Atripla, Cimduo, Complera, Delstrigo, Stribild, Symfi, Truvada, Viread •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bis(POC)PMPA •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tenofovir disoproxil is a nucleotide analog reverse transcriptase inhibitor used in the treatment of Hepatitis B infection and used in the management of HIV-1 infection.

The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Tenofovir disoproxil interact? Information: •Drug A: Bupropion •Drug B: Tenofovir disoproxil •Severity: MINOR •Description: Tenofovir disoproxil may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tenofovir disoproxil is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in patients ≥2 years old and weighing ≥10 kg. It is also indicated for the treatment of chronic hepatitis B in patients ≥2 years old and weighing ≥10 kg. Tenofovir disoproxil is also an ingredient in several combination products, all of which are indicated either alone or in combination with other antiretrovirals for the treatment of HIV-1 infection. In addition, tenofovir disoproxil is available in combination with emtricitabine (under the brand name Truvada) for use as pre-exposure prophylaxis (PrEP) in at-risk adults and adolescents weighing ≥ 35kg to reduce the risk of sexually-acquired HIV-1 infection. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): This drug prevents viral DNA chain elongation through inhibition of enzymes necessary for host cell infection viral replication in HIV-1 and Hepatitis B infections,. In vitro effects The antiviral activity of tenofovir against in laboratory and clinical isolates of HIV-1 was studied in lymphoblastoid cell lines, primary monocyte/macrophage cells, in addition to peripheral blood lymphocytes. The EC50 (50% effective concentration) values of tenofovir against HIV-1 virus ranged between 0.04 μM to 8.5 μM. Combination of tenofovir disoproxil with other drugs In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive and synergistic effects were seen. Tenofovir demonstrated antiviral activities in cell cultures against HIV-1. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tenofovir belongs to a class of antiretroviral drugs known as nucleotide analog reverse transcriptase inhibitors (NtRTIs), which block reverse transcriptase, an enzyme necessary for viral production in HIV-infected individuals. This enables the management of HIV viral load through decreased viral replication. Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to its active form, tenofovir, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, a chain terminator, by constitutively expressed enzymes in the cell. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the Hepatitis B polymerase by direct binding competition with the natural deoxyribonucleotide substrate (deoxyadenosine 5’-triphosphate) and, after integration into DNA, causes viral DNA chain termination,. A note on resistance HIV-1 isolates with decreased susceptibility to tenofovir have been identified in cell culture studies. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2– 4 fold decrease in susceptibility to treatment with tenofovir. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After oral administration of tenofovir disoproxil to patients with HIV infection, tenofovir disoproxil is quickly absorbed and metabolized to tenofovir. Administration of tenofovir disoproxil 300 mg tablets after a high-fat meal increases the oral bioavailability of this drug, as demonstrated by an increase in tenofovir AUC0-∞ of about 40% as well as an increase in Cmax of about 14%. On the contrary, the administration of tenofovir disoproxil with a light meal did not exert a relevant effect on the pharmacokinetics of tenofovir when compared to administration under fasting conditions. The presence of ingested food slows the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL after several doses of tenofovir disoproxil 300 mg once daily in the fed state when meal content is not controlled. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg. After oral administration of tenofovir disoproxil, tenofovir is distributed to the majority tissues with the highest concentrations measured in the kidney, liver and the intestinal contents (based on data from preclinical studies). •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): In vitro binding of tenofovir to human plasma or serum proteins is <0.7 and <7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to its active form, tenofovir, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, a chain terminator, by constitutively expressed enzymes in the cell. Two phosphorylation steps are required to convert tenofovir disoproxil to the active drug form. The cytochrome P450 enzyme system is not involved with the metabolism of tenofovir disoproxil or tenofovir. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also eliminated by the kidneys. •Half-life (Drug A): 24 hours •Half-life (Drug B): When a single oral dose is given, the terminal elimination half-life is approximately 17 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of tenofovir is highly dependent on renal function and may vary greatly. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min). On average, renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 210 ml/min), which is in excess of the glomerular filtration rate. This shows that active tubular secretion is an essential part of the elimination of tenofovir. The FDA label provides specific guidelines for dosing according to renal function. It is important to consult product labeling before administering tenofovir to individuals with renal dysfunction, as the clearance of this drug may vary greatly among these patients. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): A note on breastfeeding The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to prevent postnatal transmission of HIV-1. Mothers should be advised not to breast-feed if they are receiving tenofovir disoproxil. Carcinogenesis Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were performed at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the higher dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose. Pregnancy This drug is considered a pregnancy Category B drug. Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the recommended human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not consistently reflective of human effects, tenofovir disoproxil should be used during pregnancy only if clearly required. To monitor fetal outcomes of pregnant women taking tenofovir disoproxil, an Antiretroviral Pregnancy Registry has been formed. Healthcare providers are encouraged and advised to register patients by calling the number listed on the FDA label for tenofovir disoproxil. Mutagenesis Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative for mutagenesis in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice. Impairment of Fertility There were no observed effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was given to male rats at a dose comparable to 10 times the human dose based on body surface area comparisons for 28 days before mating and to female rats for 15 days before mating through day seven of gestation. There was, however, changes in the estrous cycle in female rats. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Atripla, Cimduo, Complera, Delstrigo, Stribild, Symfi, Truvada, Viread •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bis(POC)PMPA •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tenofovir disoproxil is a nucleotide analog reverse transcriptase inhibitor used in the treatment of Hepatitis B infection and used in the management of HIV-1 infection. Output: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Does Bupropion and Tenoxicam interact?

•Drug A: Bupropion •Drug B: Tenoxicam •Severity: MINOR •Description: Tenoxicam may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of rheumatoid arthritis, osteoarthritis, backache, and pain. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tenoxicam, an antiinflammatory agent with analgesic and antipyretic properties, is used to treat osteoarthritis and control acute pain. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The antiinflammatory effects of tenoxicam may result from the inhibition of the enzyme cycooxygenase and the subsequent peripheral inhibition of prostaglandin synthesis. As prostaglandins sensitize pain receptors, their inhibition accounts for the peripheral analgesic effects of tenoxicam. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Oral absorption of tenoxicam is rapid and complete (absolute bioavailability 100%). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 99% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tenoxicam is metabolized in the liver to several pharmacologically inactive metabolites (mainly 5'-hydroxy-tenoxicam). •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 72 hours (range 59 to 74 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tenoxicam is an anti inflammatory analgesic used to treat mild to moderate pain as well as the signs and symptoms of rheumatoid arthritis and osteoarthritis.

The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Tenoxicam interact? Information: •Drug A: Bupropion •Drug B: Tenoxicam •Severity: MINOR •Description: Tenoxicam may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of rheumatoid arthritis, osteoarthritis, backache, and pain. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tenoxicam, an antiinflammatory agent with analgesic and antipyretic properties, is used to treat osteoarthritis and control acute pain. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The antiinflammatory effects of tenoxicam may result from the inhibition of the enzyme cycooxygenase and the subsequent peripheral inhibition of prostaglandin synthesis. As prostaglandins sensitize pain receptors, their inhibition accounts for the peripheral analgesic effects of tenoxicam. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Oral absorption of tenoxicam is rapid and complete (absolute bioavailability 100%). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 99% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tenoxicam is metabolized in the liver to several pharmacologically inactive metabolites (mainly 5'-hydroxy-tenoxicam). •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 72 hours (range 59 to 74 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tenoxicam is an anti inflammatory analgesic used to treat mild to moderate pain as well as the signs and symptoms of rheumatoid arthritis and osteoarthritis. Output: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Does Bupropion and Tepotinib interact?

•Drug A: Bupropion •Drug B: Tepotinib •Severity: MAJOR •Description: The metabolism of Bupropion can be decreased when combined with Tepotinib. •Extended Description: The subject drug is a strong inhibitor of CYP2C9 while the affected drug is metabolized by CYP2C9. Concomitant administration will lead to an increase in serum concentrations of the affected drug, leading to accumulation of the drug and an increase in the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tepotinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) who have mesenchymal-epithelial transition ( MET ) exon 14 skipping alterations. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tepotinib is a highly-selective inhibitor of MET kinase activity, with an average IC 50 of approximately 1.7 nmol/L. It has a moderate duration of action necessitating once-daily administration. Tepotinib has been associated with the development of interstitial lung disease (ILD)/pneumonitis, which can sometimes be fatal. Patients should be monitored closely for signs of new or worsening respiratory symptoms (e.g. dyspnea, cough), and treatment with tepotinib should be immediately withheld if ILD/pneumonitis is suspected. If no other potential causes of ILD/pneumonitis are identified, therapy with tepotinib should be suspended indefinitely. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase found overexpressed and/or mutated in a variety of tumor types, thus making it a desirable target in their treatment. MET plays a critical role in the proliferation, survival, invasion, and mobilization of tumor cells, and aberrant MET activation is thought to contribute to the development of more aggressive cancers with poorer prognoses. Tepotinib is a kinase inhibitor directed against MET, including variants with exon 14 skipping - it inhibits MET phosphorylation and subsequent downstream signaling pathways in order to inhibit tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells. Tepotinib has also been observed to down-regulate the expression of epithelial-mesenchymal transition (EMT) promoting genes (e.g. MMP7, COX-2, WNT1, MUC5B, and c-MYC) and upregulate the expression of EMT-suppressing genes (e.g. MUC5AC, MUC6, GSK3β, and E-cadherin) in c-MET-amplified gastric cancer cells, suggesting that the tumor-suppressing activity of tepotinib is driven, at least in part, by the negative regulation of c-MET-induced EMT. It has also been shown to inhibit melatonin 1B and nischarin at clinically relevant concentrations, though the relevance of this activity in regards to tepotinib's mechanism of action is unclear. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The absolute bioavailability of tepotinib following oral administration is approximately 72%. At the recommended dosage of 450mg once daily, the median T max is 8 hours and the mean steady-state C max and AUC 0-24h were 1,291 ng/mL and 27,438 ng·h/mL, respectively. Co-administration with a high-fat, high-calorie meal increases the AUC and C max of tepotinib by approximately 1.6-fold and 2-fold, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean apparent volume of distribution is 1,038L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tepotinib is approximately 98% protein-bound in plasma, primarily to serum albumin and alpha-1-acid glycoprotein. Plasma protein binding is independent of drug concentration at clinically relevant exposures. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tepotinib is metabolized primarily by CYP3A4 and CYP2C8, with some apparent contribution by unspecified UGT enzymes. The metabolite M506 is the major circulating metabolite, comprising approximately 40.4% of observed drug material in plasma, while the M668 glucuronide metabolite has been observed in plasma at much lower quantities (~4% of an orally administered dose). A total of 10 phase I and phase II metabolites have been detected following tepotinib administration, most of which are excreted in the feces. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following oral administration, approximately 85% of the given dose is excreted in the feces with the remainder excreted in the urine. Unchanged parent drug accounts for roughly half of the dose excreted in the feces, with the remainder comprising the demethylated M478 metabolite, a glucuronide metabolite, the racemic M506 metabolite, and some minor oxidative metabolites. Unchanged parent drug also accounts for roughly half of the dose excreted in the urine, with the remainder comprising a glucuronide metabolite and a pair of N-oxide diastereomer metabolites. •Half-life (Drug A): 24 hours •Half-life (Drug B): Following oral administration, the half-life of tepotinib is approximately 32 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance of tepotinib is 23.8 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): There are no data regarding overdosage of tepotinib. Symptoms of overdose are likely to be consistent with tepotinib's adverse effect profile and may therefore involve significant gastrointestinal symptoms, musculoskeletal pain, and laboratory abnormalities. Treatment of overdose should involve symptomatic and supportive measures. In the event of overdose, dialysis is unlikely to be of benefit given the high degree of plasma protein binding exhibited by tepotinib. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tepmetko •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tepotinib is an oral tyrosine kinase inhibitor targeted against MET for the treatment of metastatic non-small cell lung cancer in patients exhibiting MET exon 14 skipping mutations.

The subject drug is a strong inhibitor of CYP2C9 while the affected drug is metabolized by CYP2C9. Concomitant administration will lead to an increase in serum concentrations of the affected drug, leading to accumulation of the drug and an increase in the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Tepotinib interact? Information: •Drug A: Bupropion •Drug B: Tepotinib •Severity: MAJOR •Description: The metabolism of Bupropion can be decreased when combined with Tepotinib. •Extended Description: The subject drug is a strong inhibitor of CYP2C9 while the affected drug is metabolized by CYP2C9. Concomitant administration will lead to an increase in serum concentrations of the affected drug, leading to accumulation of the drug and an increase in the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tepotinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) who have mesenchymal-epithelial transition ( MET ) exon 14 skipping alterations. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tepotinib is a highly-selective inhibitor of MET kinase activity, with an average IC 50 of approximately 1.7 nmol/L. It has a moderate duration of action necessitating once-daily administration. Tepotinib has been associated with the development of interstitial lung disease (ILD)/pneumonitis, which can sometimes be fatal. Patients should be monitored closely for signs of new or worsening respiratory symptoms (e.g. dyspnea, cough), and treatment with tepotinib should be immediately withheld if ILD/pneumonitis is suspected. If no other potential causes of ILD/pneumonitis are identified, therapy with tepotinib should be suspended indefinitely. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase found overexpressed and/or mutated in a variety of tumor types, thus making it a desirable target in their treatment. MET plays a critical role in the proliferation, survival, invasion, and mobilization of tumor cells, and aberrant MET activation is thought to contribute to the development of more aggressive cancers with poorer prognoses. Tepotinib is a kinase inhibitor directed against MET, including variants with exon 14 skipping - it inhibits MET phosphorylation and subsequent downstream signaling pathways in order to inhibit tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells. Tepotinib has also been observed to down-regulate the expression of epithelial-mesenchymal transition (EMT) promoting genes (e.g. MMP7, COX-2, WNT1, MUC5B, and c-MYC) and upregulate the expression of EMT-suppressing genes (e.g. MUC5AC, MUC6, GSK3β, and E-cadherin) in c-MET-amplified gastric cancer cells, suggesting that the tumor-suppressing activity of tepotinib is driven, at least in part, by the negative regulation of c-MET-induced EMT. It has also been shown to inhibit melatonin 1B and nischarin at clinically relevant concentrations, though the relevance of this activity in regards to tepotinib's mechanism of action is unclear. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The absolute bioavailability of tepotinib following oral administration is approximately 72%. At the recommended dosage of 450mg once daily, the median T max is 8 hours and the mean steady-state C max and AUC 0-24h were 1,291 ng/mL and 27,438 ng·h/mL, respectively. Co-administration with a high-fat, high-calorie meal increases the AUC and C max of tepotinib by approximately 1.6-fold and 2-fold, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean apparent volume of distribution is 1,038L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tepotinib is approximately 98% protein-bound in plasma, primarily to serum albumin and alpha-1-acid glycoprotein. Plasma protein binding is independent of drug concentration at clinically relevant exposures. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tepotinib is metabolized primarily by CYP3A4 and CYP2C8, with some apparent contribution by unspecified UGT enzymes. The metabolite M506 is the major circulating metabolite, comprising approximately 40.4% of observed drug material in plasma, while the M668 glucuronide metabolite has been observed in plasma at much lower quantities (~4% of an orally administered dose). A total of 10 phase I and phase II metabolites have been detected following tepotinib administration, most of which are excreted in the feces. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following oral administration, approximately 85% of the given dose is excreted in the feces with the remainder excreted in the urine. Unchanged parent drug accounts for roughly half of the dose excreted in the feces, with the remainder comprising the demethylated M478 metabolite, a glucuronide metabolite, the racemic M506 metabolite, and some minor oxidative metabolites. Unchanged parent drug also accounts for roughly half of the dose excreted in the urine, with the remainder comprising a glucuronide metabolite and a pair of N-oxide diastereomer metabolites. •Half-life (Drug A): 24 hours •Half-life (Drug B): Following oral administration, the half-life of tepotinib is approximately 32 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance of tepotinib is 23.8 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): There are no data regarding overdosage of tepotinib. Symptoms of overdose are likely to be consistent with tepotinib's adverse effect profile and may therefore involve significant gastrointestinal symptoms, musculoskeletal pain, and laboratory abnormalities. Treatment of overdose should involve symptomatic and supportive measures. In the event of overdose, dialysis is unlikely to be of benefit given the high degree of plasma protein binding exhibited by tepotinib. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tepmetko •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tepotinib is an oral tyrosine kinase inhibitor targeted against MET for the treatment of metastatic non-small cell lung cancer in patients exhibiting MET exon 14 skipping mutations. Output: The subject drug is a strong inhibitor of CYP2C9 while the affected drug is metabolized by CYP2C9. Concomitant administration will lead to an increase in serum concentrations of the affected drug, leading to accumulation of the drug and an increase in the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Terbinafine interact?

•Drug A: Bupropion •Drug B: Terbinafine •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Terbinafine. •Extended Description: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Terbinafine hydrochloride is indicated to treat fungal skin and nail infections caused by Trichophyton species, Microsporum canis, Epidermophyton floccosum, and Tinea species. Terbinafine hydrochloride also treats yeast infections of the skin caused by Candida species and Malassezia furfur. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Terbinafine is an allylamine antifungal that inhibits squalene epoxidase (also known as squalene monooxygenase) to prevent the formation of ergosterol and cause an accumulation of squalene, weakening the cell wall of fungal cells. Terbinafine distributes into tissues and has a long terminal elimination half life, so the duration of action is long. Overdose with terbinafine is rare, even above the therapeutic dose, so the therapeutic index is wide. Patients taking oral terbinafine should have liver function tests performed prior to treatment to reduce the risk of liver injury. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Terbinafine inhibits the enzyme squalene monooxygenase (also called squalene epoxidase), preventing the conversion of squalene to 2,3-oxydosqualene, a step in the synthesis of ergosterol. This inhibition leads to decreased ergosterol, which would normally be incorporated into the cell wall, and accumulation of squalene. Generation of a large number of squalene containing vesicles in the cytoplasm may leach other lipids away from, and further weaken, the cell wall. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Oral terbinafine is >70% absorbed but only 40% bioavailable after first pass metabolism, reaching a C max of 1µg/mL with a T max of 2 hours an an AUC of 4.56µg*h/mL. Over the course of a week, 1% topical terbinafine's C max increases from 949-1049ng/cm and the AUC increases from 9694-13,492ng/cm /h. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): A single 250mg oral dose of terbinafine has a volume of distribution at steady state of 947.5L or 16.6L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Terbinafine is >99% bound to proteins in plasma, mostly to serum albumin, high and low density lipoproteins, and alpha-1-acid glycoprotein to a lesser extent. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Terbinafine can be deaminated to 1-naphthaldehyde by CYP2C9, 2B6, 2C8, 1A2, 3A4, and 2C19. 1-naphthaldehyde is then oxidized to 1-naphthoic acid or reduced to 1-naphthalenemethanol. Terbinafine can also be hydroxylated by CYP1A2, 2C9, 2C8, 2B6, and 2C19 to hydroxyterbinafine. Hydroxyterbinafine is then oxidized to carboxyterbinafine or N-demethylated by CYP3A4, 2B6, 1A2, 2C9, 2C8, and 2C19 to desmethylhydroxyterbinafine. Terbinafine can be N-demethylated to desmethylterbinafine. Desmethylterbinafine is then dihydroxylated to a desmethyldihydrodiol or hydroxylated to desmethylhydroxyterbinafine. Finally, terbinafine can be dihydroxylated to a dihydrodiol which is then N-demethylated to a desmethyldihydrodiol. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Terbinafine is approximately 80% eliminated in urine, while the remainder is eliminated in feces. The unmetabolized parent drug is not present in urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Oral terbinafine has an effective half life of approximately 36 hours. However, the terminal half life ranges from 200-400 hours as it distributes into skin and adipose tissue. 1% topical terbinafine's half life increases over the first seven days from approximately 10-40 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): A single 250mg oral dose of terbinafine has a clearance of 76L/h or 1.11L/h/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The subcutaneous LD 50 in rats and mice is >2g/kg. The TDLO for women is 210mg/kg/6W. Overdose data with terbinafine is rare, however symptoms are expected to be nausea, vomiting, abdominal pain, dizziness, rash, frequent urination, and headache. Treat overdose with activated charcoal as well as symptomatic and supportive therapy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Lamisil, Silka Cream •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Terbinafina Terbinafine Terbinafinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Terbinafine is an allylamine antifungal used to treat dermatophyte infections of toenails and fingernails as well as other fungal skin infections.

Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Terbinafine interact? Information: •Drug A: Bupropion •Drug B: Terbinafine •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Terbinafine. •Extended Description: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Terbinafine hydrochloride is indicated to treat fungal skin and nail infections caused by Trichophyton species, Microsporum canis, Epidermophyton floccosum, and Tinea species. Terbinafine hydrochloride also treats yeast infections of the skin caused by Candida species and Malassezia furfur. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Terbinafine is an allylamine antifungal that inhibits squalene epoxidase (also known as squalene monooxygenase) to prevent the formation of ergosterol and cause an accumulation of squalene, weakening the cell wall of fungal cells. Terbinafine distributes into tissues and has a long terminal elimination half life, so the duration of action is long. Overdose with terbinafine is rare, even above the therapeutic dose, so the therapeutic index is wide. Patients taking oral terbinafine should have liver function tests performed prior to treatment to reduce the risk of liver injury. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Terbinafine inhibits the enzyme squalene monooxygenase (also called squalene epoxidase), preventing the conversion of squalene to 2,3-oxydosqualene, a step in the synthesis of ergosterol. This inhibition leads to decreased ergosterol, which would normally be incorporated into the cell wall, and accumulation of squalene. Generation of a large number of squalene containing vesicles in the cytoplasm may leach other lipids away from, and further weaken, the cell wall. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Oral terbinafine is >70% absorbed but only 40% bioavailable after first pass metabolism, reaching a C max of 1µg/mL with a T max of 2 hours an an AUC of 4.56µg*h/mL. Over the course of a week, 1% topical terbinafine's C max increases from 949-1049ng/cm and the AUC increases from 9694-13,492ng/cm /h. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): A single 250mg oral dose of terbinafine has a volume of distribution at steady state of 947.5L or 16.6L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Terbinafine is >99% bound to proteins in plasma, mostly to serum albumin, high and low density lipoproteins, and alpha-1-acid glycoprotein to a lesser extent. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Terbinafine can be deaminated to 1-naphthaldehyde by CYP2C9, 2B6, 2C8, 1A2, 3A4, and 2C19. 1-naphthaldehyde is then oxidized to 1-naphthoic acid or reduced to 1-naphthalenemethanol. Terbinafine can also be hydroxylated by CYP1A2, 2C9, 2C8, 2B6, and 2C19 to hydroxyterbinafine. Hydroxyterbinafine is then oxidized to carboxyterbinafine or N-demethylated by CYP3A4, 2B6, 1A2, 2C9, 2C8, and 2C19 to desmethylhydroxyterbinafine. Terbinafine can be N-demethylated to desmethylterbinafine. Desmethylterbinafine is then dihydroxylated to a desmethyldihydrodiol or hydroxylated to desmethylhydroxyterbinafine. Finally, terbinafine can be dihydroxylated to a dihydrodiol which is then N-demethylated to a desmethyldihydrodiol. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Terbinafine is approximately 80% eliminated in urine, while the remainder is eliminated in feces. The unmetabolized parent drug is not present in urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Oral terbinafine has an effective half life of approximately 36 hours. However, the terminal half life ranges from 200-400 hours as it distributes into skin and adipose tissue. 1% topical terbinafine's half life increases over the first seven days from approximately 10-40 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): A single 250mg oral dose of terbinafine has a clearance of 76L/h or 1.11L/h/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The subcutaneous LD 50 in rats and mice is >2g/kg. The TDLO for women is 210mg/kg/6W. Overdose data with terbinafine is rare, however symptoms are expected to be nausea, vomiting, abdominal pain, dizziness, rash, frequent urination, and headache. Treat overdose with activated charcoal as well as symptomatic and supportive therapy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Lamisil, Silka Cream •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Terbinafina Terbinafine Terbinafinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Terbinafine is an allylamine antifungal used to treat dermatophyte infections of toenails and fingernails as well as other fungal skin infections. Output: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. The severity of the interaction is minor.

Does Bupropion and Terbutaline interact?

•Drug A: Bupropion •Drug B: Terbutaline •Severity: MINOR •Description: Terbutaline may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Terbutaline is indicated for prevention and reversal of bronchospasm in patients at least 12 years old, with asthma and reversible bronchospasm associated with bronchitis and emphysema. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Terbutaline is a beta-2 adrenergic receptor agonist indicated to treat reversibly bronchospasm in asthmatic patients with bronchitis and emphysema. It has a short duration as the inhaled form is taken up to three times daily, and the therapeutic window is wide. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Terbutaline is a selective beta-2 adrenergic receptor agonist. Agonism of these receptors in bronchioles activates adenylyl cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP). Increased cAMP decreases intracellular calcium, activating protein kinase A, inactivating myosin light-chain kinase, activating myosin light-chain phosphatase, and finally relaxing smooth muscle in the bronchiole. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): A 0.5 mg subcutaneous dose of terbutaline reaches a mean C max of 9.6 ± ng/mL, with a median T max of 0.5 hours, and a mean AUC of 29.4 ± 14.2 h*ng/mL. A 5 mg oral terbutaline tablet reaches a mean C max of 8.3 ± 3.9 ng/mL with a median T max of 2 hours, and a mean AUC of 54.6 ± 26.8 h*ng/mL. A 5 mg oral terbutaline solution reaches a mean C max of 8.6 ± 3.6 ng/mL, with a median T max of 1.5 hours, and a mean AUC of 53.1 ± 23.5 h*ng/mL. Oral terbutaline has an oral bioavailability of 14-15%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Terbutaline has a mean volume of distribution of 1.6 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Terbutaline is not highly bound to protein in plasma. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Terbutaline is sulphated or glucuronidated prior to elimination. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): An oral dose of terbutaline is 40% eliminated in the urine after 72 hours. The major metabolite in the urine was the sulphate conjugated form of terbutaline. Parenteral doses of terbutaline are 90% eliminated in the urine, with approximately 2/3 as the unchanged parent drug. Less than 1% of a dose of terbutaline is eliminated in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): An oral dose of terbutaline has an elimination half life of 3.4 hours, while a subcutaneous dose has an elimination half life of 2.9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average clearance of terbutaline is 3.0 mL/min/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Patients experiencing an overdose may present with abdominal pain, agitation, palpitations, seizures, angina, hypertension, hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, nausea, dizziness, fatigue, malaise, insomnia. Discontinue treatment with terbutaline and initiate symptomatic and supportive therapy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Bricanyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Terbutaline is a beta-2 adrenergic agonist used as a bronchodilator and to prevent premature labor.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Terbutaline interact? Information: •Drug A: Bupropion •Drug B: Terbutaline •Severity: MINOR •Description: Terbutaline may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Terbutaline is indicated for prevention and reversal of bronchospasm in patients at least 12 years old, with asthma and reversible bronchospasm associated with bronchitis and emphysema. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Terbutaline is a beta-2 adrenergic receptor agonist indicated to treat reversibly bronchospasm in asthmatic patients with bronchitis and emphysema. It has a short duration as the inhaled form is taken up to three times daily, and the therapeutic window is wide. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Terbutaline is a selective beta-2 adrenergic receptor agonist. Agonism of these receptors in bronchioles activates adenylyl cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP). Increased cAMP decreases intracellular calcium, activating protein kinase A, inactivating myosin light-chain kinase, activating myosin light-chain phosphatase, and finally relaxing smooth muscle in the bronchiole. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): A 0.5 mg subcutaneous dose of terbutaline reaches a mean C max of 9.6 ± ng/mL, with a median T max of 0.5 hours, and a mean AUC of 29.4 ± 14.2 h*ng/mL. A 5 mg oral terbutaline tablet reaches a mean C max of 8.3 ± 3.9 ng/mL with a median T max of 2 hours, and a mean AUC of 54.6 ± 26.8 h*ng/mL. A 5 mg oral terbutaline solution reaches a mean C max of 8.6 ± 3.6 ng/mL, with a median T max of 1.5 hours, and a mean AUC of 53.1 ± 23.5 h*ng/mL. Oral terbutaline has an oral bioavailability of 14-15%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Terbutaline has a mean volume of distribution of 1.6 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Terbutaline is not highly bound to protein in plasma. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Terbutaline is sulphated or glucuronidated prior to elimination. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): An oral dose of terbutaline is 40% eliminated in the urine after 72 hours. The major metabolite in the urine was the sulphate conjugated form of terbutaline. Parenteral doses of terbutaline are 90% eliminated in the urine, with approximately 2/3 as the unchanged parent drug. Less than 1% of a dose of terbutaline is eliminated in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): An oral dose of terbutaline has an elimination half life of 3.4 hours, while a subcutaneous dose has an elimination half life of 2.9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average clearance of terbutaline is 3.0 mL/min/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Patients experiencing an overdose may present with abdominal pain, agitation, palpitations, seizures, angina, hypertension, hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, nausea, dizziness, fatigue, malaise, insomnia. Discontinue treatment with terbutaline and initiate symptomatic and supportive therapy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Bricanyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Terbutaline is a beta-2 adrenergic agonist used as a bronchodilator and to prevent premature labor. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Terfenadine interact?

•Drug A: Bupropion •Drug B: Terfenadine •Severity: MAJOR •Description: The metabolism of Terfenadine can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of allergic rhinitis, hay fever, and allergic skin disorders. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Terfenadine, an H1-receptor antagonist antihistamine, is similar in structure to astemizole and haloperidol, a butyrophenone antipsychotic. The active metabolite of terfenadine is fexofenadine. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Terfenadine competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of terfenadine to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier, CNS depression is minimal. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): On the basis of a mass balance study using 14C labeled terfenadine the oral absorption of terfenadine was estimated to be at least 70% •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 70% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 3.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Mild (e.g., headache, nausea, confusion), but adverse cardiac events including cardiac arrest, ventricular arrhythmias including torsades de pointes and QT prolongation have been reported. LD 50 =mg/kg (orally in mice) •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Terfenadin Terfenadina Terfénadine Terfenadine Terfenadinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Terfenadine is an antihistamine for the treatment of allergy symptoms.

The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Terfenadine interact? Information: •Drug A: Bupropion •Drug B: Terfenadine •Severity: MAJOR •Description: The metabolism of Terfenadine can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of allergic rhinitis, hay fever, and allergic skin disorders. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Terfenadine, an H1-receptor antagonist antihistamine, is similar in structure to astemizole and haloperidol, a butyrophenone antipsychotic. The active metabolite of terfenadine is fexofenadine. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Terfenadine competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of terfenadine to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier, CNS depression is minimal. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): On the basis of a mass balance study using 14C labeled terfenadine the oral absorption of terfenadine was estimated to be at least 70% •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 70% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 3.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Mild (e.g., headache, nausea, confusion), but adverse cardiac events including cardiac arrest, ventricular arrhythmias including torsades de pointes and QT prolongation have been reported. LD 50 =mg/kg (orally in mice) •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Terfenadin Terfenadina Terfénadine Terfenadine Terfenadinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Terfenadine is an antihistamine for the treatment of allergy symptoms. Output: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Testosterone cypionate interact?

•Drug A: Bupropion •Drug B: Testosterone cypionate •Severity: MODERATE •Description: The metabolism of Testosterone cypionate can be decreased when combined with Bupropion. •Extended Description: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Testosterone cypionate is used in males that present conditions derived from a deficiency or absence of endogenous testosterone. These conditions are 1) primary hypogonadism, defined as the testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; and 2) hypogonadotropic hypogonadism characterized by idiopathic gonadotropin, LHRH deficiency or pituitary-hypothalamic injury from tumors, trauma or radiation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Administration of ester derivatives of testosterone as testosterone cypionate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. The continuous variation in plasma testosterone after intramuscular administration of testosterone cypionate results in fluctuations in mood and libido as well as some local inflammation. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5-alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Testosterone cypionate is an esterified anabolic which allows it to present a greater degree of solubility in fats and thus, the release and absorption occur in a slow rate compare to homologous molecules. Intramuscular administration of 200 mg of testosterone cypionate produced a mean supratherapeutic Cmax of 1122 ng/dl which occurred 4-5 days post-injection. After the fifth day, the levels of testosterone cypionate in plasma went down reaching an average of 400 ng/dl. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Testosterone cypionate, following conversion into testosterone, is approximately 98% protein-bound to sex hormone-binding globulin in plasma. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): To start its activity, testosterone cypionate has to be processed by enzymes in the bloodstream. These enzymes will break the bond between the cypionate ester moiety and the testosterone. Once separated, testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half-life of testosterone cypionate is one of the longest, being approximately of 8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Testosterone cypionate presents a lower clearance rate after intramuscular administration compared to other analogs of testosterone. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Preclinical studies with testosterone implants induced cervical-uterine tumors in mice which metastasized in some cases. Some reports indicate that administration of testosterone cypionate in females can augment the susceptibility to hepatoma as well as increase the number of tumors. Clinical studies have reported cases of hepatocellular carcinoma in long-term high-dose therapy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Depo-testosterone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosterone cipionate Testosterone cyclopentanepropionate Testosterone cyclopentylpropionate Testosterone cypionate •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Testosterone cypionate is an androgen used to treat low or absent testosterone.

When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. The severity of the interaction is moderate.

Question: Does Bupropion and Testosterone cypionate interact? Information: •Drug A: Bupropion •Drug B: Testosterone cypionate •Severity: MODERATE •Description: The metabolism of Testosterone cypionate can be decreased when combined with Bupropion. •Extended Description: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Testosterone cypionate is used in males that present conditions derived from a deficiency or absence of endogenous testosterone. These conditions are 1) primary hypogonadism, defined as the testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; and 2) hypogonadotropic hypogonadism characterized by idiopathic gonadotropin, LHRH deficiency or pituitary-hypothalamic injury from tumors, trauma or radiation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Administration of ester derivatives of testosterone as testosterone cypionate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. The continuous variation in plasma testosterone after intramuscular administration of testosterone cypionate results in fluctuations in mood and libido as well as some local inflammation. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5-alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Testosterone cypionate is an esterified anabolic which allows it to present a greater degree of solubility in fats and thus, the release and absorption occur in a slow rate compare to homologous molecules. Intramuscular administration of 200 mg of testosterone cypionate produced a mean supratherapeutic Cmax of 1122 ng/dl which occurred 4-5 days post-injection. After the fifth day, the levels of testosterone cypionate in plasma went down reaching an average of 400 ng/dl. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Testosterone cypionate, following conversion into testosterone, is approximately 98% protein-bound to sex hormone-binding globulin in plasma. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): To start its activity, testosterone cypionate has to be processed by enzymes in the bloodstream. These enzymes will break the bond between the cypionate ester moiety and the testosterone. Once separated, testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half-life of testosterone cypionate is one of the longest, being approximately of 8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Testosterone cypionate presents a lower clearance rate after intramuscular administration compared to other analogs of testosterone. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Preclinical studies with testosterone implants induced cervical-uterine tumors in mice which metastasized in some cases. Some reports indicate that administration of testosterone cypionate in females can augment the susceptibility to hepatoma as well as increase the number of tumors. Clinical studies have reported cases of hepatocellular carcinoma in long-term high-dose therapy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Depo-testosterone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosterone cipionate Testosterone cyclopentanepropionate Testosterone cyclopentylpropionate Testosterone cypionate •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Testosterone cypionate is an androgen used to treat low or absent testosterone. Output: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. The severity of the interaction is moderate.

Does Bupropion and Testosterone enanthate interact?

•Drug A: Bupropion •Drug B: Testosterone enanthate •Severity: MODERATE •Description: The metabolism of Testosterone enanthate can be decreased when combined with Bupropion. •Extended Description: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Testosterone enanthate in males is indicated as a replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. Some of the treated conditions are 1) primary hypogonadism, defined as testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; 2) hypogonadotropic hypogonadism due to an idiopathic gonadotropin or luteinizing hormone-releasing hormone deficiency or due to a pituitary-hypothalamic injury from tumors, trauma or radiation, in this case it is important to accompany the treatment with adrenal cortical and thyroid hormone replacement therapy; 3) to stimulate puberty in patients with delayed puberty not secondary to a pathological disorder. If the conditions 1 and 2 occur prior to puberty, the androgen replacement therapy will be needed during adolescent years for the development of secondary sexual characteristics and prolonged androgen treatment might be needed it to maintain sexual characteristics after puberty. In females, testosterone enanthate is indicated to be used secondarily in presence of advanced inoperable metastatic mammary cancer in women who are from one to five years postmenopausal. It has also been used in premenopausal women with breast cancer who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. Testosterone enanthate injections that are currently formulated for subcutaneous use are specifically indicated only for primary hypogonadism and hypogonadotropic hypogonadism. The use of such formulations is limited because the safety and efficacy of these subcutaneous products in adult males with late-onset hypogonadism and males less than 18 years old have not yet been established. Moreover, subcutaneously administered testosterone enanthate is indicated only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies, considering the medication could cause blood pressure increases that can raise the risk of major adverse cardiovascular events like non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Administration of ester derivatives of testosterone as testosterone enanthate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. Continuous administration of testosterone enanthate shows a significant suppression of dihydrotestosterone, serum PSA, HDL and FSH, as well as a slight increase in serum estradiol. The levels of dihydrotestosterone and FSH can remain suppressed even 14 days after treatment termination. There are no changes in mood and sexual activity by the presence of testosterone enanthate. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5α-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing androgen effects. Such activities are useful as endogenous androgens like testosterone and dihydrotestosterone are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The pharmacokinetic profile of testosterone enanthate was studied in a regime of multiple dosing and the testosterone level was reported to present a Cmax above 1200 ng/dl after 24 hours of the last dose. The concentration decreased sequentially until it reached 600 ng/dl after one week. The pharmacokinetic profile of testosterone enanthate presented differences depending on the administered dose in which the tmax was shifted to a range of 36-48 hours. The plasma testosterone level plateaued below the therapeutic range after 3-4 weeks. This reports showed that the different formulation of testosterone enanthate and testosterone cypionate generates a different profile and thus, they are not therapeutically equivalent. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Circulating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 98% of testosterone in plasma is bound to SHBG while 2% remains unbound (i.e. free). •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): To start its activity, testosterone enanthate has to be processed by enzymes in the bloodstream. These enzymes will catalyze the molecule at the ester location of the moiety. Once processed in this manner, the testosterone enanthate molecule is metabolized to various 17-keto steroids through two different pathways. Subsequently, the major active metabolites are estradiol and DHTd. Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. The inactivation of testosterone occurs primarily in the liver. •Half-life (Drug A): 24 hours •Half-life (Drug B): Testosterone enanthate presents a long half-life in the range of 7-9 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Testosterone enanthate has been tested in preclinical carcinogenesis trials. In this studies, it is suggested that the exposure to this drug may increase the susceptibility to hematoma as well as the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver. Testosterone enanthate is not indicated for use in females and is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action. During treatment with large doses of exogenous androgens, including testosterone enanthate, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis. Reduced fertility is observed in some men taking testosterone replacement therapy and the impact on fertility may be irreversible. Safety and effectiveness of testosterone enanthate in pediatric patients less than 18 years old have not been established. Improper use may result in the acceleration of bone age and premature closure of epiphyses. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of Benign Prostatic Hyperplasia. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Delatestryl, Xyosted •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Testosterone enanthate is an androgen used to treat low or absent testosterone.

When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. The severity of the interaction is moderate.

Question: Does Bupropion and Testosterone enanthate interact? Information: •Drug A: Bupropion •Drug B: Testosterone enanthate •Severity: MODERATE •Description: The metabolism of Testosterone enanthate can be decreased when combined with Bupropion. •Extended Description: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Testosterone enanthate in males is indicated as a replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. Some of the treated conditions are 1) primary hypogonadism, defined as testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; 2) hypogonadotropic hypogonadism due to an idiopathic gonadotropin or luteinizing hormone-releasing hormone deficiency or due to a pituitary-hypothalamic injury from tumors, trauma or radiation, in this case it is important to accompany the treatment with adrenal cortical and thyroid hormone replacement therapy; 3) to stimulate puberty in patients with delayed puberty not secondary to a pathological disorder. If the conditions 1 and 2 occur prior to puberty, the androgen replacement therapy will be needed during adolescent years for the development of secondary sexual characteristics and prolonged androgen treatment might be needed it to maintain sexual characteristics after puberty. In females, testosterone enanthate is indicated to be used secondarily in presence of advanced inoperable metastatic mammary cancer in women who are from one to five years postmenopausal. It has also been used in premenopausal women with breast cancer who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. Testosterone enanthate injections that are currently formulated for subcutaneous use are specifically indicated only for primary hypogonadism and hypogonadotropic hypogonadism. The use of such formulations is limited because the safety and efficacy of these subcutaneous products in adult males with late-onset hypogonadism and males less than 18 years old have not yet been established. Moreover, subcutaneously administered testosterone enanthate is indicated only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies, considering the medication could cause blood pressure increases that can raise the risk of major adverse cardiovascular events like non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Administration of ester derivatives of testosterone as testosterone enanthate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. Continuous administration of testosterone enanthate shows a significant suppression of dihydrotestosterone, serum PSA, HDL and FSH, as well as a slight increase in serum estradiol. The levels of dihydrotestosterone and FSH can remain suppressed even 14 days after treatment termination. There are no changes in mood and sexual activity by the presence of testosterone enanthate. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5α-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing androgen effects. Such activities are useful as endogenous androgens like testosterone and dihydrotestosterone are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The pharmacokinetic profile of testosterone enanthate was studied in a regime of multiple dosing and the testosterone level was reported to present a Cmax above 1200 ng/dl after 24 hours of the last dose. The concentration decreased sequentially until it reached 600 ng/dl after one week. The pharmacokinetic profile of testosterone enanthate presented differences depending on the administered dose in which the tmax was shifted to a range of 36-48 hours. The plasma testosterone level plateaued below the therapeutic range after 3-4 weeks. This reports showed that the different formulation of testosterone enanthate and testosterone cypionate generates a different profile and thus, they are not therapeutically equivalent. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Circulating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 98% of testosterone in plasma is bound to SHBG while 2% remains unbound (i.e. free). •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): To start its activity, testosterone enanthate has to be processed by enzymes in the bloodstream. These enzymes will catalyze the molecule at the ester location of the moiety. Once processed in this manner, the testosterone enanthate molecule is metabolized to various 17-keto steroids through two different pathways. Subsequently, the major active metabolites are estradiol and DHTd. Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. The inactivation of testosterone occurs primarily in the liver. •Half-life (Drug A): 24 hours •Half-life (Drug B): Testosterone enanthate presents a long half-life in the range of 7-9 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Testosterone enanthate has been tested in preclinical carcinogenesis trials. In this studies, it is suggested that the exposure to this drug may increase the susceptibility to hematoma as well as the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver. Testosterone enanthate is not indicated for use in females and is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action. During treatment with large doses of exogenous androgens, including testosterone enanthate, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis. Reduced fertility is observed in some men taking testosterone replacement therapy and the impact on fertility may be irreversible. Safety and effectiveness of testosterone enanthate in pediatric patients less than 18 years old have not been established. Improper use may result in the acceleration of bone age and premature closure of epiphyses. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of Benign Prostatic Hyperplasia. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Delatestryl, Xyosted •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Testosterone enanthate is an androgen used to treat low or absent testosterone. Output: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. The severity of the interaction is moderate.

Does Bupropion and Testosterone propionate interact?

•Drug A: Bupropion •Drug B: Testosterone propionate •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Testosterone propionate which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Testosterone propionate is used in veterinary practice in heifers in order to stimulate maximal growth. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): The administration of testosterone propionate can induce production of proteins related to male sexual development. Clinical trials have shown a decrease in plasma LH after the administration of testosterone propionate. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5alpha-reductase. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Testosterone propionate presents a slow absorption from the intramuscular site of administration. This slow absorption is due to the presence of the less polar ester group. The absorption rate of testosterone propionate generates a frequent injection requirement when compared with testosterone enanthate or testosterone cypionate. It presents absorption parameters of AUC and residence time of 180-210 ng h/ml and 40-60 h, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The registered volume of distribution for testosterone propionate is in the range of 75-120 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Even 98% of testosterone in plasma is bound to sex hormone-binding globulin and 2% remains unbound or bound to albumin and other proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): As all testosterone esters, testosterone propionate is rapidly hydrolysed into free testosterone in plasma. Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites. From the rest of the dose, approximately 6% of a dose is excreted in the feces, mostly in the unconjugated form. •Half-life (Drug A): 24 hours •Half-life (Drug B): Testosterone propionate possesses a relatively short half-life compared with other testosterone esters at approximately 4.5 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Testosterone propionate has a reduced clearance rate compared to testosterone. The reported clearance rate is of approximately 2000 ml/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Reports have showed a potential stimulation of cancerous tissue growth. The potential testosterone propionate accumulation in the body produces a high risk of edema secondaryh to water and sodium retention. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Testosterone propionate is a slow-release anabolic steroid no longer used commonly for the treatment of androgen deficiency or promotion of anabolic effects on muscles.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Testosterone propionate interact? Information: •Drug A: Bupropion •Drug B: Testosterone propionate •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Testosterone propionate which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Testosterone propionate is used in veterinary practice in heifers in order to stimulate maximal growth. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): The administration of testosterone propionate can induce production of proteins related to male sexual development. Clinical trials have shown a decrease in plasma LH after the administration of testosterone propionate. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5alpha-reductase. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Testosterone propionate presents a slow absorption from the intramuscular site of administration. This slow absorption is due to the presence of the less polar ester group. The absorption rate of testosterone propionate generates a frequent injection requirement when compared with testosterone enanthate or testosterone cypionate. It presents absorption parameters of AUC and residence time of 180-210 ng h/ml and 40-60 h, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The registered volume of distribution for testosterone propionate is in the range of 75-120 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Even 98% of testosterone in plasma is bound to sex hormone-binding globulin and 2% remains unbound or bound to albumin and other proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): As all testosterone esters, testosterone propionate is rapidly hydrolysed into free testosterone in plasma. Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites. From the rest of the dose, approximately 6% of a dose is excreted in the feces, mostly in the unconjugated form. •Half-life (Drug A): 24 hours •Half-life (Drug B): Testosterone propionate possesses a relatively short half-life compared with other testosterone esters at approximately 4.5 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Testosterone propionate has a reduced clearance rate compared to testosterone. The reported clearance rate is of approximately 2000 ml/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Reports have showed a potential stimulation of cancerous tissue growth. The potential testosterone propionate accumulation in the body produces a high risk of edema secondaryh to water and sodium retention. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Testosterone propionate is a slow-release anabolic steroid no longer used commonly for the treatment of androgen deficiency or promotion of anabolic effects on muscles. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Testosterone undecanoate interact?

•Drug A: Bupropion •Drug B: Testosterone undecanoate •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Testosterone undecanoate which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Testosterone undecanoate is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. These conditions include: Congenital or acquired primary hypogonadism: testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter’s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone FSH, luteinizing hormone LH ) above the normal range. Congenital or acquired hypogonadotropic hypogonadism: gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Testosterone undecanoate is not used to treat age-related hypogonadism. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Once in circulation, testosterone undecanoate is cleaved to release testosterone, which mediates a range of biological actions. Testosterone is an endogenous male hormone that plays a key role in male sexual differentiation: it is involved in the regulation of hematopoiesis, body composition, and bone metabolism. As a hormone replacement therapy, testosterone undecanoate is an exogenous source of testosterone in males with hypogonadism. Testosterone therapy aims to improve symptoms and signs of testosterone deficiency including decreased libido, erectile dysfunction, and loss of muscle and bone mass. Testosterone has a controlled substance in the US due to the abuse potential by athletes and bodybuilders. The use of testosterone at higher doses than recommended can lead to withdrawal symptoms lasting for weeks or months. Withdrawal symptoms include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido, and hypogonadotropic hypogonadism. Testosterone can cause hirsutism, virilization, deepening of the voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities when administered to women. The use in adolescents can lead to the premature closure of bony epiphyses with termination of growth and precocious puberty. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Testosterone is a critical male sex hormone that is responsible for the normal growth and development of the male sex organs and the maintenance of secondary sex characteristics, such as the growth and maturation of male sex organs, the development of male hair distribution, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, resulting from insufficient testosterone secretion, has two main etiologies: primary hypogonadism is caused by defects in the gonads, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH and LH). In the circulation, testosterone undecanoate is cleaved by endogenous non-specific esterases to release testosterone, the active component of the compound. The undecanoate side chain is pharmacologically inactive. Testosterone can be further converted by 5α reductase to its more biologically active form, dihydrotestosterone (DHT). The actions of testosterone and DHT are mediated via androgen receptor, which is widely expressed in many tissues, including the bone, muscle, prostate, and adipose tissue. Testosterone binds to androgen receptors with high affinity and regulates target gene transcription involved in the normal growth and development of the male sex organs and the maintenance of secondary sex characteristics. Testosterone can cause improved sexual function, increased lean body mass, bone density, erythropoiesis, prostate size, and changes in lipid profiles. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Testosterone undecanoate is a lipophilic molecule that is absorbed into the intestinal lymphatic system after oral administration. It is then released into the general blood circulation by the thoracic duct, thereby bypassing the portal circulation and first-pass metabolism in the liver, unlike endogenous testosterone. Following oral administration of 237 mg twice per day in males with hypogonadism, the mean (SD) C max was 1008 (581) ng/dL. T max is about five hours following oral administration. Decreased testosterone exposure was observed when administered without food. Following intramuscular administration of 750 mg testosterone undecanoate, serum testosterone concentrations reached a maximum after a median of seven days (range of four to 42 days), which then slowly declined. The mean (SD) C max was about 90.9 (68.8) ng/dL on the fourth day following injection of testosterone undecanoate. Steady-state serum testosterone concentration was achieved with the third injection at 14 weeks. At 42 days following the injection, testosterone undecanoate was nearly undetectable. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): There is no information available. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): About 40% of circulating testosterone is bound to sex hormone-binding globulin (SHBG) and about 2% of the drug remains unbound to plasma proteins. The rest is loosely bound to albumin and other plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Testosterone undecanoate can be reduced to dihydrotestosterone undecanoate via 5α-reductase. In the circulation, the ester bond linking testosterone to the undecanoic acid is cleaved by endogenous non-specific esterases. Like all fatty acids, the undecanoic side chain undergoes β-oxidation to form acetyl coenzyme A (CoA) and, finally, propionyl CoA. Testosterone is metabolized to various 17-keto steroids through two different pathways to form major active metabolites, estradiol and dihydrotestosterone (DHT). •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 90% of a testosterone dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of testosterone or as metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life of testosterone undecanoate is approximately two hours. Once testosterone is formed from testosterone undecanoate, the half life of testosterone can vary and the reported values in the literature remain inconsistent, ranging from 10 to to 100 minutes. Testosterone undecanoate in castor oil for intramuscular injection had a half life of 33.9 days, allowing it to maintain serum levels in the normal range for over 6 weeks.[A176954] •Clearance (Drug A): No clearance available •Clearance (Drug B): While there is limited information available, an earlier study reports a metabolic clearance rate of 24.5 mL/min/kg for testosterone following oral administration of 25 mg testosterone and 40 mg testosterone undecanoate in women. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 is 4000 mg/kg in mice and rats. The subcutaneous LD 50 is 2880 mg/kg in mice and rats. There is limited information on testosterone undecanoate overdose. There was one report of acute overdose from an approved injectable testosterone product, which resulted in increased serum testosterone levels of up to 11,400 ng/dL with a cerebrovascular accident. There was one case of overdose following administration of oral testosterone undecanoate capsules: this patient inadvertently took a 20% higher dose than the maximum recommended dose but did not report any adverse reactions. Overdose should be managed with discontinuation of the drug in combination with appropriate symptomatic and supportive care. The abuse of anabolic androgenic steroids can result in serious adverse reactions, such as cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility, and aggression. Men receiving testosterone have experienced transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Aveed, Jatenzo, Kyzatrex, Tlando •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Testosterone undecanoate is an androgen indicated for testosterone replacement therapy in adult males with primary hypogonadism and hypogonadotropic hypogonadism.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Testosterone undecanoate interact? Information: •Drug A: Bupropion •Drug B: Testosterone undecanoate •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Testosterone undecanoate which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Testosterone undecanoate is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. These conditions include: Congenital or acquired primary hypogonadism: testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter’s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone FSH, luteinizing hormone LH ) above the normal range. Congenital or acquired hypogonadotropic hypogonadism: gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Testosterone undecanoate is not used to treat age-related hypogonadism. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Once in circulation, testosterone undecanoate is cleaved to release testosterone, which mediates a range of biological actions. Testosterone is an endogenous male hormone that plays a key role in male sexual differentiation: it is involved in the regulation of hematopoiesis, body composition, and bone metabolism. As a hormone replacement therapy, testosterone undecanoate is an exogenous source of testosterone in males with hypogonadism. Testosterone therapy aims to improve symptoms and signs of testosterone deficiency including decreased libido, erectile dysfunction, and loss of muscle and bone mass. Testosterone has a controlled substance in the US due to the abuse potential by athletes and bodybuilders. The use of testosterone at higher doses than recommended can lead to withdrawal symptoms lasting for weeks or months. Withdrawal symptoms include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido, and hypogonadotropic hypogonadism. Testosterone can cause hirsutism, virilization, deepening of the voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities when administered to women. The use in adolescents can lead to the premature closure of bony epiphyses with termination of growth and precocious puberty. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Testosterone is a critical male sex hormone that is responsible for the normal growth and development of the male sex organs and the maintenance of secondary sex characteristics, such as the growth and maturation of male sex organs, the development of male hair distribution, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, resulting from insufficient testosterone secretion, has two main etiologies: primary hypogonadism is caused by defects in the gonads, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH and LH). In the circulation, testosterone undecanoate is cleaved by endogenous non-specific esterases to release testosterone, the active component of the compound. The undecanoate side chain is pharmacologically inactive. Testosterone can be further converted by 5α reductase to its more biologically active form, dihydrotestosterone (DHT). The actions of testosterone and DHT are mediated via androgen receptor, which is widely expressed in many tissues, including the bone, muscle, prostate, and adipose tissue. Testosterone binds to androgen receptors with high affinity and regulates target gene transcription involved in the normal growth and development of the male sex organs and the maintenance of secondary sex characteristics. Testosterone can cause improved sexual function, increased lean body mass, bone density, erythropoiesis, prostate size, and changes in lipid profiles. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Testosterone undecanoate is a lipophilic molecule that is absorbed into the intestinal lymphatic system after oral administration. It is then released into the general blood circulation by the thoracic duct, thereby bypassing the portal circulation and first-pass metabolism in the liver, unlike endogenous testosterone. Following oral administration of 237 mg twice per day in males with hypogonadism, the mean (SD) C max was 1008 (581) ng/dL. T max is about five hours following oral administration. Decreased testosterone exposure was observed when administered without food. Following intramuscular administration of 750 mg testosterone undecanoate, serum testosterone concentrations reached a maximum after a median of seven days (range of four to 42 days), which then slowly declined. The mean (SD) C max was about 90.9 (68.8) ng/dL on the fourth day following injection of testosterone undecanoate. Steady-state serum testosterone concentration was achieved with the third injection at 14 weeks. At 42 days following the injection, testosterone undecanoate was nearly undetectable. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): There is no information available. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): About 40% of circulating testosterone is bound to sex hormone-binding globulin (SHBG) and about 2% of the drug remains unbound to plasma proteins. The rest is loosely bound to albumin and other plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Testosterone undecanoate can be reduced to dihydrotestosterone undecanoate via 5α-reductase. In the circulation, the ester bond linking testosterone to the undecanoic acid is cleaved by endogenous non-specific esterases. Like all fatty acids, the undecanoic side chain undergoes β-oxidation to form acetyl coenzyme A (CoA) and, finally, propionyl CoA. Testosterone is metabolized to various 17-keto steroids through two different pathways to form major active metabolites, estradiol and dihydrotestosterone (DHT). •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 90% of a testosterone dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of testosterone or as metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life of testosterone undecanoate is approximately two hours. Once testosterone is formed from testosterone undecanoate, the half life of testosterone can vary and the reported values in the literature remain inconsistent, ranging from 10 to to 100 minutes. Testosterone undecanoate in castor oil for intramuscular injection had a half life of 33.9 days, allowing it to maintain serum levels in the normal range for over 6 weeks.[A176954] •Clearance (Drug A): No clearance available •Clearance (Drug B): While there is limited information available, an earlier study reports a metabolic clearance rate of 24.5 mL/min/kg for testosterone following oral administration of 25 mg testosterone and 40 mg testosterone undecanoate in women. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 is 4000 mg/kg in mice and rats. The subcutaneous LD 50 is 2880 mg/kg in mice and rats. There is limited information on testosterone undecanoate overdose. There was one report of acute overdose from an approved injectable testosterone product, which resulted in increased serum testosterone levels of up to 11,400 ng/dL with a cerebrovascular accident. There was one case of overdose following administration of oral testosterone undecanoate capsules: this patient inadvertently took a 20% higher dose than the maximum recommended dose but did not report any adverse reactions. Overdose should be managed with discontinuation of the drug in combination with appropriate symptomatic and supportive care. The abuse of anabolic androgenic steroids can result in serious adverse reactions, such as cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility, and aggression. Men receiving testosterone have experienced transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Aveed, Jatenzo, Kyzatrex, Tlando •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Testosterone undecanoate is an androgen indicated for testosterone replacement therapy in adult males with primary hypogonadism and hypogonadotropic hypogonadism. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Testosterone interact?

•Drug A: Bupropion •Drug B: Testosterone •Severity: MINOR •Description: Testosterone may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Testosterone is indicated to treat primary hypogonadism and hypogonadotropic hypogonadism. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Testosterone antagonizes the androgen receptor to induce gene expression that causes the growth and development of masculine sex organs and secondary sexual characteristics. The duration of action of testosterone is variable from patient to patient with a half life of 10-100 minutes. The therapeutic index is wide considering the normal testosterone levels in an adult man range from 300-1000ng/dL. Counsel patients regarding the risk of secondary exposure of testosterone topical products to children. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The androgen receptor exists in the cytoplasm bound to the heat shock proteins HSP90, HSP70, and other chaperones. After binding to an androgen, the androgen receptor dissociates from HSP90 and undergoes a conformational change to slow the rate of dissociation from the androgen receptor. The androgen-receptor complex is transported into the nucleus where it binds to DNA and recruits other transcriptional regulators to form a pre-initiation complex and eventually induce expression of specific genes. Testosterone and its active metabolite dihydrotestosterone (DHT) antagonize the androgen receptor to develop masculine sex organs including the prostate, seminal vesicles, penis, and scrotum. Antagonism of the androgen receptor is also responsible for the development of secondary sexual characteristics including facial and body hair, enlargement of the larynx, thickening of the vocal cords, and changes in muscle and fat distribution. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): A single 100mg topical dose of testosterone has an AUC of 10425±5521ng*h/dL and a C max of 573±284ng/dL. Testosterone is approximately 10% bioavailable topically. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of testosterone in elderly men is 80.36±24.51L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Testosterone is 40% bound to sex hormone binding globulin, 2% unbound, and the remainder is bound to albumin and other proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone can be hydroxylated at a number of positions by CYP3A4, CYP2B6, CYP2C9, and CYP2C19; glucuronidated by UGT2B17; sulfated; converted to estradiol by aromatase; converted to dihydrotestosterone (DHT) by 5α-reductase; metabolized to androstenedione by CYP3A4, CYP2C9, and CYP2C19; or converted to DHT glucuronide. Androstenedione undergoes metabolism by aromatase to form estrone, which undergoes a reversible reaction to form estradiol. Androstenedione can also be converted to 5α-androstanedione by 5α-reductase, which can be further metabolized to 5α-androsterone. DHT can be glucuronidated or sulfated, or metabolized to 5α-androstanediol, androstane-3α,17β-diol, or androstane-3β,17β-diol. DHT can also be reversibly converted to 5α-androstanedione. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): 90% of an intramuscular dose is eliminated in urine, mainly as glucuronide and sulfate conjugates. 6% is eliminated in feces, mostly as unconjugated metabolites. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half life of testosterone is highly variable, ranging from 10-100 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean metabolic clearance in middle aged men is 812±64L/day. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Data regarding an overdose with a topical testosterone product is not readily available. In the case of overdose with an injectable product, patients may present with a cerebrovascular event. Treat overdoses by stopping testosterone products, washing off any topical products with soap and water, and initiating symptomatic and supportive treatments. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Androderm, Androgel, Axiron, Fortesta, Natesto, Striant, Testim, Testopel, Vogelxo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosteron Testosterona Testostérone Testosterone Testosteronum Virosterone •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Testosterone is a hormone used to treat hypogonadism, breast carcinoma in women, or the vasomotor symptoms of menopause.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Testosterone interact? Information: •Drug A: Bupropion •Drug B: Testosterone •Severity: MINOR •Description: Testosterone may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Testosterone is indicated to treat primary hypogonadism and hypogonadotropic hypogonadism. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Testosterone antagonizes the androgen receptor to induce gene expression that causes the growth and development of masculine sex organs and secondary sexual characteristics. The duration of action of testosterone is variable from patient to patient with a half life of 10-100 minutes. The therapeutic index is wide considering the normal testosterone levels in an adult man range from 300-1000ng/dL. Counsel patients regarding the risk of secondary exposure of testosterone topical products to children. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The androgen receptor exists in the cytoplasm bound to the heat shock proteins HSP90, HSP70, and other chaperones. After binding to an androgen, the androgen receptor dissociates from HSP90 and undergoes a conformational change to slow the rate of dissociation from the androgen receptor. The androgen-receptor complex is transported into the nucleus where it binds to DNA and recruits other transcriptional regulators to form a pre-initiation complex and eventually induce expression of specific genes. Testosterone and its active metabolite dihydrotestosterone (DHT) antagonize the androgen receptor to develop masculine sex organs including the prostate, seminal vesicles, penis, and scrotum. Antagonism of the androgen receptor is also responsible for the development of secondary sexual characteristics including facial and body hair, enlargement of the larynx, thickening of the vocal cords, and changes in muscle and fat distribution. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): A single 100mg topical dose of testosterone has an AUC of 10425±5521ng*h/dL and a C max of 573±284ng/dL. Testosterone is approximately 10% bioavailable topically. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of testosterone in elderly men is 80.36±24.51L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Testosterone is 40% bound to sex hormone binding globulin, 2% unbound, and the remainder is bound to albumin and other proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone can be hydroxylated at a number of positions by CYP3A4, CYP2B6, CYP2C9, and CYP2C19; glucuronidated by UGT2B17; sulfated; converted to estradiol by aromatase; converted to dihydrotestosterone (DHT) by 5α-reductase; metabolized to androstenedione by CYP3A4, CYP2C9, and CYP2C19; or converted to DHT glucuronide. Androstenedione undergoes metabolism by aromatase to form estrone, which undergoes a reversible reaction to form estradiol. Androstenedione can also be converted to 5α-androstanedione by 5α-reductase, which can be further metabolized to 5α-androsterone. DHT can be glucuronidated or sulfated, or metabolized to 5α-androstanediol, androstane-3α,17β-diol, or androstane-3β,17β-diol. DHT can also be reversibly converted to 5α-androstanedione. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): 90% of an intramuscular dose is eliminated in urine, mainly as glucuronide and sulfate conjugates. 6% is eliminated in feces, mostly as unconjugated metabolites. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half life of testosterone is highly variable, ranging from 10-100 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean metabolic clearance in middle aged men is 812±64L/day. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Data regarding an overdose with a topical testosterone product is not readily available. In the case of overdose with an injectable product, patients may present with a cerebrovascular event. Treat overdoses by stopping testosterone products, washing off any topical products with soap and water, and initiating symptomatic and supportive treatments. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Androderm, Androgel, Axiron, Fortesta, Natesto, Striant, Testim, Testopel, Vogelxo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosteron Testosterona Testostérone Testosterone Testosteronum Virosterone •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Testosterone is a hormone used to treat hypogonadism, breast carcinoma in women, or the vasomotor symptoms of menopause. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Tetrabenazine interact?

•Drug A: Bupropion •Drug B: Tetrabenazine •Severity: MODERATE •Description: The metabolism of Tetrabenazine can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and tetrabenazine is metabolized by CYP2D6. Concomitant administration can reduce the metabolism of tetrabenazine, raising serum concentrations and increasing the risk and severity of adverse reactions like QTc prolongation. However, a single 50mg dose of tetrabenazine has not been shown to increase the QTc interval. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients; Tmax, oral = 69 min in HD or tardive dyskinesia patients •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Steady State, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazine is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tetrabenazine = 82 - 88%; α-HTBZ = 60 - 68%; β-HTBZ = 59 - 63%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). α-HTBZ is further metabolized into 9-desmethyl-α-DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. β-HTBZ is metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazine is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) accounted for less than 10% of the administered dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): There is interindividual variability in elimination half-life. The elimination half-life of tetrabenazine was 10 hours following intravenous bolus administration. The oral half-lives of its metabolites, α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are seven hours, five hours and 12 hours, respectively. Following a single oral dose of 25 mg tetrabenazine, the elimination half-life was approximately 17.5 hours in subjects with hepatic impairment. •Clearance (Drug A): No clearance available •Clearance (Drug B): IV, 1.67 L/min in HD or tardive dyskinesia patients •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Dose-limiting adverse effects are sedation, parkinsonism, akathsia, and depression. LD50 oral, mouse: 550 mg/kg •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Nitoman, Xenazine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tetrabenazina Tetrabenazine Tetrabenazinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tetrabenazine is a vesicular monoamine transporter 2 (VMAT) inhibitor used for the management of chorea associated with Huntington's Disease.

The subject drug is a strong CYP2D6 inhibitor and tetrabenazine is metabolized by CYP2D6. Concomitant administration can reduce the metabolism of tetrabenazine, raising serum concentrations and increasing the risk and severity of adverse reactions like QTc prolongation. However, a single 50mg dose of tetrabenazine has not been shown to increase the QTc interval. The severity of the interaction is moderate.

Question: Does Bupropion and Tetrabenazine interact? Information: •Drug A: Bupropion •Drug B: Tetrabenazine •Severity: MODERATE •Description: The metabolism of Tetrabenazine can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and tetrabenazine is metabolized by CYP2D6. Concomitant administration can reduce the metabolism of tetrabenazine, raising serum concentrations and increasing the risk and severity of adverse reactions like QTc prolongation. However, a single 50mg dose of tetrabenazine has not been shown to increase the QTc interval. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients; Tmax, oral = 69 min in HD or tardive dyskinesia patients •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Steady State, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazine is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tetrabenazine = 82 - 88%; α-HTBZ = 60 - 68%; β-HTBZ = 59 - 63%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). α-HTBZ is further metabolized into 9-desmethyl-α-DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. β-HTBZ is metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazine is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) accounted for less than 10% of the administered dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): There is interindividual variability in elimination half-life. The elimination half-life of tetrabenazine was 10 hours following intravenous bolus administration. The oral half-lives of its metabolites, α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are seven hours, five hours and 12 hours, respectively. Following a single oral dose of 25 mg tetrabenazine, the elimination half-life was approximately 17.5 hours in subjects with hepatic impairment. •Clearance (Drug A): No clearance available •Clearance (Drug B): IV, 1.67 L/min in HD or tardive dyskinesia patients •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Dose-limiting adverse effects are sedation, parkinsonism, akathsia, and depression. LD50 oral, mouse: 550 mg/kg •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Nitoman, Xenazine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tetrabenazina Tetrabenazine Tetrabenazinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tetrabenazine is a vesicular monoamine transporter 2 (VMAT) inhibitor used for the management of chorea associated with Huntington's Disease. Output: The subject drug is a strong CYP2D6 inhibitor and tetrabenazine is metabolized by CYP2D6. Concomitant administration can reduce the metabolism of tetrabenazine, raising serum concentrations and increasing the risk and severity of adverse reactions like QTc prolongation. However, a single 50mg dose of tetrabenazine has not been shown to increase the QTc interval. The severity of the interaction is moderate.

Does Bupropion and Tetracaine interact?

•Drug A: Bupropion •Drug B: Tetracaine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Bupropion is combined with Tetracaine. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Ophthalmic tetracaine is indicated for the for procedures requiring a rapid and short- acting topical ophthalmic anesthetic. The combination lidocaine and tetracaine patch is indicated for local dermal analgesia for superficial dermatological procedures and superficial venous access. The combination lidocaine and tetracaine cream is intended to provide topical local analgesia for superficial dermatological procedures. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tetracaine is an ester-type anesthetic and produces local anesthesia by blocking the sodium ion channels involved in the initiation and conduction of neuronal impulses. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Systemic absorption of anaesthetic from the combination cream is directly related to the duration and surface area of application. Although peak plasma concentrations for lidocaine were measured, plasma levels for tetracaine could not be determined due to low levels (<0.9 ng/mL) •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Tetracaine is rapidly hydrolyzed in the plasma; therefore, volume of distribution could not be determined. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tetracaine is rapidly hydrolyzed in the plasma; therefore, protein binding could not be determined. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tetracaine is rapidly hydrolyzed by plasma esterases to the following primary metabolites: para-aminobenzoic acid and diethylaminoethanol. The activity of both metabolites is unspecified. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): Tetracaine is hydrolyzed rapidly in the plasma; therefore, half-life has not been determined. •Clearance (Drug A): No clearance available •Clearance (Drug B): Tetracaine is hydrolyzed rapidly in the plasma; therefore, clearance has not been determined. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The most common adverse effects with the combination cream are localized reactions such as: erythema (47%), skin discoloration (16%), and edema (14%). Systemic adverse events were less common, occurring at a rate of <1% and included vomiting, headache, dizziness, and fever. Similar to other amide and ester anesthetics, CNS excitation and/or depression may occur. It is not well known at which plasma concentration systemic toxicity occurs with tetracaine; however, the threshold is thought to be much lower than that of lidocaine which is 1000 ng/mL. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Ametop, Cetacaine, Kovanaze, One Touch Reformulated Apr 2009, Pliaglis, Synera, Zap •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amethocaine Amethocaine HCl Diäthylaminoäthanol ester der p-butylaminobenzösäure Dicaine Medihaler-Tetracaine Metraspray Tetracaína Tétracaïne Tetracaine Tetracaine HCl •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tetracaine is a local anaesthetic agent used to induce local analgesia in the eyes and skin during medical procedures.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Tetracaine interact? Information: •Drug A: Bupropion •Drug B: Tetracaine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Bupropion is combined with Tetracaine. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Ophthalmic tetracaine is indicated for the for procedures requiring a rapid and short- acting topical ophthalmic anesthetic. The combination lidocaine and tetracaine patch is indicated for local dermal analgesia for superficial dermatological procedures and superficial venous access. The combination lidocaine and tetracaine cream is intended to provide topical local analgesia for superficial dermatological procedures. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tetracaine is an ester-type anesthetic and produces local anesthesia by blocking the sodium ion channels involved in the initiation and conduction of neuronal impulses. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Systemic absorption of anaesthetic from the combination cream is directly related to the duration and surface area of application. Although peak plasma concentrations for lidocaine were measured, plasma levels for tetracaine could not be determined due to low levels (<0.9 ng/mL) •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Tetracaine is rapidly hydrolyzed in the plasma; therefore, volume of distribution could not be determined. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tetracaine is rapidly hydrolyzed in the plasma; therefore, protein binding could not be determined. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tetracaine is rapidly hydrolyzed by plasma esterases to the following primary metabolites: para-aminobenzoic acid and diethylaminoethanol. The activity of both metabolites is unspecified. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): Tetracaine is hydrolyzed rapidly in the plasma; therefore, half-life has not been determined. •Clearance (Drug A): No clearance available •Clearance (Drug B): Tetracaine is hydrolyzed rapidly in the plasma; therefore, clearance has not been determined. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The most common adverse effects with the combination cream are localized reactions such as: erythema (47%), skin discoloration (16%), and edema (14%). Systemic adverse events were less common, occurring at a rate of <1% and included vomiting, headache, dizziness, and fever. Similar to other amide and ester anesthetics, CNS excitation and/or depression may occur. It is not well known at which plasma concentration systemic toxicity occurs with tetracaine; however, the threshold is thought to be much lower than that of lidocaine which is 1000 ng/mL. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Ametop, Cetacaine, Kovanaze, One Touch Reformulated Apr 2009, Pliaglis, Synera, Zap •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amethocaine Amethocaine HCl Diäthylaminoäthanol ester der p-butylaminobenzösäure Dicaine Medihaler-Tetracaine Metraspray Tetracaína Tétracaïne Tetracaine Tetracaine HCl •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tetracaine is a local anaesthetic agent used to induce local analgesia in the eyes and skin during medical procedures. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Tetracycline interact?

•Drug A: Bupropion •Drug B: Tetracycline •Severity: MINOR •Description: Tetracycline may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Used to treat bacterial infections such as Rocky Mountain spotted fever, typhus fever, tick fevers, Q fever, rickettsialpox and Brill-Zinsser disease. May be used to treat infections caused by Chlamydiae spp., B. burgdorferi (Lyme disease), and upper respiratory infections caused by typical (S. pneumoniae, H. influenzae, and M. catarrhalis) and atypical organisms (C. pneumoniae, M. pneumoniae, L. pneumophila). May also be used to treat acne. Tetracycline may be an alternative drug for people who are allergic to penicillin. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tetracycline is a short-acting antibiotic that inhibits bacterial growth by inhibiting translation. It binds to the 30S ribosomal subunit and prevents the amino-acyl tRNA from binding to the A site of the ribosome. It also binds to some extent to the 50S ribosomal subunit. This binding is reversible in nature. Additionally tetracycline may alter the cytoplasmic membrane of bacteria causing leakage of intracellular contents, such as nucleotides, from the cell. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tetracycline passively diffuses through porin channels in the bacterial membrane and reversibly binds to the 30S ribosomal subunit, preventing binding of tRNA to the mRNA-ribosome complex, and thus interfering with protein synthesis. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Bioavailability is less than 40% when administered via intramuscular injection, 100% intravenously, and 60-80% orally (fasting adults). Food and/or milk reduce GI absorption of oral preparations of tetracycline by 50% or more. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 20 - 67% protein bound •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Not metabolized •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. •Half-life (Drug A): 24 hours •Half-life (Drug B): 6-12 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD 50 =808mg/kg (orally in mice) •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Pylera, Sumycin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Abramycin Anhydrotetracycline Deschlorobiomycin Tetracyclin Tétracycline Tetracycline Tetracyclinum Tetrazyklin Tsiklomitsin •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tetracycline is an antibiotic used to treat a wide variety of susceptible infections.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Tetracycline interact? Information: •Drug A: Bupropion •Drug B: Tetracycline •Severity: MINOR •Description: Tetracycline may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Used to treat bacterial infections such as Rocky Mountain spotted fever, typhus fever, tick fevers, Q fever, rickettsialpox and Brill-Zinsser disease. May be used to treat infections caused by Chlamydiae spp., B. burgdorferi (Lyme disease), and upper respiratory infections caused by typical (S. pneumoniae, H. influenzae, and M. catarrhalis) and atypical organisms (C. pneumoniae, M. pneumoniae, L. pneumophila). May also be used to treat acne. Tetracycline may be an alternative drug for people who are allergic to penicillin. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tetracycline is a short-acting antibiotic that inhibits bacterial growth by inhibiting translation. It binds to the 30S ribosomal subunit and prevents the amino-acyl tRNA from binding to the A site of the ribosome. It also binds to some extent to the 50S ribosomal subunit. This binding is reversible in nature. Additionally tetracycline may alter the cytoplasmic membrane of bacteria causing leakage of intracellular contents, such as nucleotides, from the cell. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tetracycline passively diffuses through porin channels in the bacterial membrane and reversibly binds to the 30S ribosomal subunit, preventing binding of tRNA to the mRNA-ribosome complex, and thus interfering with protein synthesis. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Bioavailability is less than 40% when administered via intramuscular injection, 100% intravenously, and 60-80% orally (fasting adults). Food and/or milk reduce GI absorption of oral preparations of tetracycline by 50% or more. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 20 - 67% protein bound •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Not metabolized •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. •Half-life (Drug A): 24 hours •Half-life (Drug B): 6-12 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD 50 =808mg/kg (orally in mice) •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Pylera, Sumycin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Abramycin Anhydrotetracycline Deschlorobiomycin Tetracyclin Tétracycline Tetracycline Tetracyclinum Tetrazyklin Tsiklomitsin •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tetracycline is an antibiotic used to treat a wide variety of susceptible infections. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Tetradecyl hydrogen sulfate (ester) interact?

•Drug A: Bupropion •Drug B: Tetradecyl hydrogen sulfate (ester) •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Tetradecyl hydrogen sulfate (ester) which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Sotradecol (sodium tetradecyl sulfate injection) is indicated in the treatment of small, uncomplicated varicose veins of the legs showing simple dilation, with competent valves. Sodium tetradecyl sulfate has been designated as an orphan drug by the FDA for the treatment of gastrointestinal bleeding due to esophageal varices. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Telangiectasias or varicose veins occur in about 33% of adult women and about 15% of adult men. Sclerotherapy with sotradecol is widely used in the treatment of varicose veins. Sotradecol (sodium tetradecyl sulfate injection) is a sclerosing agent. Intravenous (IV) injection of this agent causes blood vessel intima inflammation and thrombus formation. This normally occludes the injected vein, leading to a series of events. Subsequent formation of fibrous tissue results in partial or complete vein obliteration that may be temporary or permanent. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): When injected directly into a vein, sodium tetradecyl sulfate causes intimal inflammation and venous thrombus formation, which then results in occlusion of the vein. Following this sequence of events, fibrous tissue forms and causes partial to complete obliteration of the vein, which may be temporary or permanent. An important role of this drug, as well as other sclerosing agents, is to control active hemorrhage and encourage hemostasis. This may be due to the esophageal and vascular smooth muscle spasm induced by the sclerosing agent. During acute and active bleeding, the sodium tetradecyl sulfate injected directly into the esophageal varices may dissipate rapidly, as the varices have a much higher blood volume/flow rate and no functioning valves. The mechanical compression effect of submucosal edema, created by the injection of sclerosing agents, may also be responsible for acute hemostasis. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In humans, a large proportion (75%) of an injected dose of radiolabelled 3% sodium tetradecyl sulfate rapidly disappeared from the empty varicose vein injection site into communicating blood vessels with rapid entry into the deep veins of the calf. In rats, at 72 hours after intravenous dosing of radiolabelled sodium tetradecyl sulfate, tissue levels of radiolabelled matter found in sample tissues (liver, kidney, lipid and skeletal muscle) were measured as very low. Although there was some evidence of radiolabel associated with the injection site, the levels were negligible. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): After an intravenously administered radiolabelled dose, 70% of the drug was recovered in the urine of rats within 24 hours post-dosing. At the end of the 72 hour post-dose period, 73.5% of the radiolabel had been recovered from the urine and 18.2% recovered from the faeces. •Half-life (Drug A): 24 hours •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The intravenous LD50 of sodium tetradecyl sulfate in mice is 90 ± 5 mg/kg. In the rat, the acute intravenous LD50 of sodium tetradecyl sulfate is estimated at 72 mg/kg and 108 mg/kg. Adverse events are below: Deep venous thrombosis Because of the risk of deep vein thrombosis, patients must be evaluated for valvular competency and deep venous patency before treatment is initiated and slow injections of a small volume (< 2 mL) should be injected. It is recommended that patients be monitored post-treatment for both deep vein thrombosis and pulmonary embolism. Air embolism Stroke, transient ischemic attack, myocardial infarction, and impaired cardiac function have been associated with tetradecyl sulfate administration. Such sequelae may be caused by air embolism. Local reaction Local reactions including pain, itching or ulceration at the site of injection with permanent discoloration may remain along the path of the treated/sclerosed vein segment. Sloughing and/or necrosis of surrounding tissue may occur following extravasation from the injection site. Allergic reactions Hives, asthma, hay fever and anaphylactic shock have been reported with use of this drug. * Mild systemic reactions * Headache, nausea and vomiting. Death A minimum of 6 deaths have reported with the use of Sotradecol. Four incidences of anaphylactic shock resulting in death have been reported in patients who received this drug. One death has been reported in a patient who received Sotradecol while receiving an anti-ovulatory agent Another death (from lethal pulmonary embolism) has been reported in a 36-year-old female treated with sodium tetradecyl acetate and was not taking oral contraceptive therapy •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Sotradecol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tetradecyl hydrogen sulfate •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tetradecyl hydrogen sulfate (ester) is an anionic surfactant used to treat small uncomplicated varicose veins.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Tetradecyl hydrogen sulfate (ester) interact? Information: •Drug A: Bupropion •Drug B: Tetradecyl hydrogen sulfate (ester) •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Tetradecyl hydrogen sulfate (ester) which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Sotradecol (sodium tetradecyl sulfate injection) is indicated in the treatment of small, uncomplicated varicose veins of the legs showing simple dilation, with competent valves. Sodium tetradecyl sulfate has been designated as an orphan drug by the FDA for the treatment of gastrointestinal bleeding due to esophageal varices. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Telangiectasias or varicose veins occur in about 33% of adult women and about 15% of adult men. Sclerotherapy with sotradecol is widely used in the treatment of varicose veins. Sotradecol (sodium tetradecyl sulfate injection) is a sclerosing agent. Intravenous (IV) injection of this agent causes blood vessel intima inflammation and thrombus formation. This normally occludes the injected vein, leading to a series of events. Subsequent formation of fibrous tissue results in partial or complete vein obliteration that may be temporary or permanent. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): When injected directly into a vein, sodium tetradecyl sulfate causes intimal inflammation and venous thrombus formation, which then results in occlusion of the vein. Following this sequence of events, fibrous tissue forms and causes partial to complete obliteration of the vein, which may be temporary or permanent. An important role of this drug, as well as other sclerosing agents, is to control active hemorrhage and encourage hemostasis. This may be due to the esophageal and vascular smooth muscle spasm induced by the sclerosing agent. During acute and active bleeding, the sodium tetradecyl sulfate injected directly into the esophageal varices may dissipate rapidly, as the varices have a much higher blood volume/flow rate and no functioning valves. The mechanical compression effect of submucosal edema, created by the injection of sclerosing agents, may also be responsible for acute hemostasis. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In humans, a large proportion (75%) of an injected dose of radiolabelled 3% sodium tetradecyl sulfate rapidly disappeared from the empty varicose vein injection site into communicating blood vessels with rapid entry into the deep veins of the calf. In rats, at 72 hours after intravenous dosing of radiolabelled sodium tetradecyl sulfate, tissue levels of radiolabelled matter found in sample tissues (liver, kidney, lipid and skeletal muscle) were measured as very low. Although there was some evidence of radiolabel associated with the injection site, the levels were negligible. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): After an intravenously administered radiolabelled dose, 70% of the drug was recovered in the urine of rats within 24 hours post-dosing. At the end of the 72 hour post-dose period, 73.5% of the radiolabel had been recovered from the urine and 18.2% recovered from the faeces. •Half-life (Drug A): 24 hours •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The intravenous LD50 of sodium tetradecyl sulfate in mice is 90 ± 5 mg/kg. In the rat, the acute intravenous LD50 of sodium tetradecyl sulfate is estimated at 72 mg/kg and 108 mg/kg. Adverse events are below: Deep venous thrombosis Because of the risk of deep vein thrombosis, patients must be evaluated for valvular competency and deep venous patency before treatment is initiated and slow injections of a small volume (< 2 mL) should be injected. It is recommended that patients be monitored post-treatment for both deep vein thrombosis and pulmonary embolism. Air embolism Stroke, transient ischemic attack, myocardial infarction, and impaired cardiac function have been associated with tetradecyl sulfate administration. Such sequelae may be caused by air embolism. Local reaction Local reactions including pain, itching or ulceration at the site of injection with permanent discoloration may remain along the path of the treated/sclerosed vein segment. Sloughing and/or necrosis of surrounding tissue may occur following extravasation from the injection site. Allergic reactions Hives, asthma, hay fever and anaphylactic shock have been reported with use of this drug. * Mild systemic reactions * Headache, nausea and vomiting. Death A minimum of 6 deaths have reported with the use of Sotradecol. Four incidences of anaphylactic shock resulting in death have been reported in patients who received this drug. One death has been reported in a patient who received Sotradecol while receiving an anti-ovulatory agent Another death (from lethal pulmonary embolism) has been reported in a 36-year-old female treated with sodium tetradecyl acetate and was not taking oral contraceptive therapy •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Sotradecol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tetradecyl hydrogen sulfate •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tetradecyl hydrogen sulfate (ester) is an anionic surfactant used to treat small uncomplicated varicose veins. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Thalidomide interact?

•Drug A: Bupropion •Drug B: Thalidomide •Severity: MAJOR •Description: Bupropion may increase the central nervous system depressant (CNS depressant) activities of Thalidomide. •Extended Description: Coadministration of thalidomide with other CNS depressants, including alcohol, may cause an additive sedative effect, which can lead to serious respiratory depression and death. Thalidomide is a neurotoxic drug with effects that may be potentiated with CNS depressants. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Thalidomide is primarily used for the acute treatment and maintenance therapy to prevent and suppress the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (−)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of thalidomide is not fully understood. Previous research indicate that thalidomide binds to cerebron, a component of the E3 ubiquitin ligase complex, to selectively degrade the transcription factor IKZF3 and IKZF1. These 2 transcription factors are vital for the proliferation and survival of malignant myeloma cells. Regarding TNF-alpha, thalidomide seems to block this mediator via a variety of mechanism. Thalidomide can inhibit the expression myeloid differentiating factor 88 (MyD88), an adaptor protein that is involved in the TNF-alpha production signalling pathway, at the protein and RNA level. Additionally, thalidomide prevents the activation of Nuclear Factor Kappa B (NF-kB), another upstream effector of the TNF-alpha production pathway. Finally, some evidences suggest that thalidomide can block alpha-1 acid glycoprotein (AGP), a known inducer of the NF-kB/MyD88 pathway, thus inhibiting the expression of TNF-alpha. The down-regulation of NF-kB and MyD88 can also affect the cross talk between the NF-kB/MyD88 and VEGF pathway, resulting in thalidomide's anti-angiogenic effect. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (T max ) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown. Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a t lag of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, c max and AUC ∞ were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The mean plasma protein binding is 55% and 66% for the (+)R and (−)S enantiomers, respectively. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH. Evidences for enzymatic metabolism of thalidomide is mixed, as in vitro studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of omeprazole, a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment. However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half-life of thalidomide in healthy male subjects after a single dose of 200 mg is 6.17 ± 2.56 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The oral clearance of thalidomide is 10.50 ± 2.10 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 in rats is 113 mg/kg and 2 g/kg in mouse. Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA). Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test. Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25- fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA). There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Thalomid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Talidomida Thalidomide Thalidomidum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thalidomide is a medication used to treat cancers, particularly newly diagnosed multiple myeloma, and erythema nodosum leprosum.

Coadministration of thalidomide with other CNS depressants, including alcohol, may cause an additive sedative effect, which can lead to serious respiratory depression and death. Thalidomide is a neurotoxic drug with effects that may be potentiated with CNS depressants. The severity of the interaction is major.

Question: Does Bupropion and Thalidomide interact? Information: •Drug A: Bupropion •Drug B: Thalidomide •Severity: MAJOR •Description: Bupropion may increase the central nervous system depressant (CNS depressant) activities of Thalidomide. •Extended Description: Coadministration of thalidomide with other CNS depressants, including alcohol, may cause an additive sedative effect, which can lead to serious respiratory depression and death. Thalidomide is a neurotoxic drug with effects that may be potentiated with CNS depressants. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Thalidomide is primarily used for the acute treatment and maintenance therapy to prevent and suppress the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (−)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of thalidomide is not fully understood. Previous research indicate that thalidomide binds to cerebron, a component of the E3 ubiquitin ligase complex, to selectively degrade the transcription factor IKZF3 and IKZF1. These 2 transcription factors are vital for the proliferation and survival of malignant myeloma cells. Regarding TNF-alpha, thalidomide seems to block this mediator via a variety of mechanism. Thalidomide can inhibit the expression myeloid differentiating factor 88 (MyD88), an adaptor protein that is involved in the TNF-alpha production signalling pathway, at the protein and RNA level. Additionally, thalidomide prevents the activation of Nuclear Factor Kappa B (NF-kB), another upstream effector of the TNF-alpha production pathway. Finally, some evidences suggest that thalidomide can block alpha-1 acid glycoprotein (AGP), a known inducer of the NF-kB/MyD88 pathway, thus inhibiting the expression of TNF-alpha. The down-regulation of NF-kB and MyD88 can also affect the cross talk between the NF-kB/MyD88 and VEGF pathway, resulting in thalidomide's anti-angiogenic effect. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (T max ) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown. Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a t lag of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, c max and AUC ∞ were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The mean plasma protein binding is 55% and 66% for the (+)R and (−)S enantiomers, respectively. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH. Evidences for enzymatic metabolism of thalidomide is mixed, as in vitro studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of omeprazole, a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment. However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half-life of thalidomide in healthy male subjects after a single dose of 200 mg is 6.17 ± 2.56 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The oral clearance of thalidomide is 10.50 ± 2.10 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 in rats is 113 mg/kg and 2 g/kg in mouse. Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA). Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test. Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25- fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA). There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Thalomid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Talidomida Thalidomide Thalidomidum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thalidomide is a medication used to treat cancers, particularly newly diagnosed multiple myeloma, and erythema nodosum leprosum. Output: Coadministration of thalidomide with other CNS depressants, including alcohol, may cause an additive sedative effect, which can lead to serious respiratory depression and death. Thalidomide is a neurotoxic drug with effects that may be potentiated with CNS depressants. The severity of the interaction is major.

Does Bupropion and Theophylline interact?

•Drug A: Bupropion •Drug B: Theophylline •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Theophylline. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, such as emphysema and chronic bronchitis. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Theophylline, an xanthine derivative chemically similar to caffeine and theobromine, is used to treat asthma and bronchospasm. Theophylline has two distinct actions in the airways of patients with reversible (asthmatic) obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 0.3 to 0.7 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 40%, primarily to albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. •Half-life (Drug A): 24 hours •Half-life (Drug B): 8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.29 mL/kg/min [Premature neonates, postnatal age 3-15 days] 0.64 mL/kg/min [Premature neonates, postnatal age 25-57 days] 1.7 mL/kg/min [Children 1-4 years] 1.6 mL/kg/min [Children 4-12 years] 0.9 mL/kg/min [Children 13-15 years] 1.4 mL/kg/min [Children 16-17 years] 0.65 mL/kg/min [Adults (16-60 years), otherwise healthy non-smoking asthmatics] 0.41 mL/kg/min [Elderly (>60 years), non-smokers with normal cardiac, liver, and renal function] 0.33 mL/kg/min [Acute pulmonary edema] 0.54 mL/kg/min [COPD >60 years, stable, non-smoker >1 year] 0.48 mL/kg/min [COPD with cor pulmonale] 1.25 mL/kg/min [Cystic fibrosis (14-28 years)] 0.31 mL/kg/min [Liver disease cirrhosis] 0.35 mL/kg/min [acute hepatitis] 0.65 mL/kg/min [cholestasis] 0.47 mL/kg/min [Sepsis with multi-organ failure] 0.38 mL/kg/min [hypothyroid] 0.8 mL/kg/min [hyperthyroid] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include seizures, arrhythmias, and GI effects. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Elixophyllin, Elixophylline, Pulmophylline, Quibron-T, Theo-24, Theolair, Uniphyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Teofilina Theophyllin •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Theophylline is a xanthine used to manage the symptoms of asthma, COPD, and other lung conditions caused by reversible airflow obstruction.

Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Question: Does Bupropion and Theophylline interact? Information: •Drug A: Bupropion •Drug B: Theophylline •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Theophylline. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, such as emphysema and chronic bronchitis. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Theophylline, an xanthine derivative chemically similar to caffeine and theobromine, is used to treat asthma and bronchospasm. Theophylline has two distinct actions in the airways of patients with reversible (asthmatic) obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 0.3 to 0.7 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 40%, primarily to albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. •Half-life (Drug A): 24 hours •Half-life (Drug B): 8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.29 mL/kg/min [Premature neonates, postnatal age 3-15 days] 0.64 mL/kg/min [Premature neonates, postnatal age 25-57 days] 1.7 mL/kg/min [Children 1-4 years] 1.6 mL/kg/min [Children 4-12 years] 0.9 mL/kg/min [Children 13-15 years] 1.4 mL/kg/min [Children 16-17 years] 0.65 mL/kg/min [Adults (16-60 years), otherwise healthy non-smoking asthmatics] 0.41 mL/kg/min [Elderly (>60 years), non-smokers with normal cardiac, liver, and renal function] 0.33 mL/kg/min [Acute pulmonary edema] 0.54 mL/kg/min [COPD >60 years, stable, non-smoker >1 year] 0.48 mL/kg/min [COPD with cor pulmonale] 1.25 mL/kg/min [Cystic fibrosis (14-28 years)] 0.31 mL/kg/min [Liver disease cirrhosis] 0.35 mL/kg/min [acute hepatitis] 0.65 mL/kg/min [cholestasis] 0.47 mL/kg/min [Sepsis with multi-organ failure] 0.38 mL/kg/min [hypothyroid] 0.8 mL/kg/min [hyperthyroid] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include seizures, arrhythmias, and GI effects. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Elixophyllin, Elixophylline, Pulmophylline, Quibron-T, Theo-24, Theolair, Uniphyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Teofilina Theophyllin •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Theophylline is a xanthine used to manage the symptoms of asthma, COPD, and other lung conditions caused by reversible airflow obstruction. Output: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Does Bupropion and Thiethylperazine interact?

•Drug A: Bupropion •Drug B: Thiethylperazine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Thiethylperazine is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment or relief of nausea and vomiting. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Thiethylperazine, an atypical antipsychotic agent, is used to treat both negative and positive symptoms of schizophrenia, acute mania with bipolar disorder, agitation, and psychotic symptoms in dementia. Future uses may include the treatment of obsessive-compulsive disorder and severe behavioral disorders in autism. Structurally and pharmacologically similar to clozapine, Thiethylperazine binds to alpha(1), dopamine, histamine H1, muscarinic, and serotonin type 2 (5-HT2) receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Thiethylperazine is an antagonist at types 1, 2, and 4 dopamine receptors, 5-HT receptor types 2A and 2C, muscarinic receptors 1 through 5, alpha(1)-receptors, and histamine H1-receptors. Thiethylperazine's antipsychotic effect is due to antagonism at dopamine and serotonin type 2 receptors, with greater activity at serotonin 5-HT2 receptors than at dopamine type-2 receptors. This may explain the lack of extrapyramidal effects. Thiethylperazine does not appear to block dopamine within the tubero-infundibular tract, explaining the lower incidence of hyperprolactinemia than with typical antipsychotic agents or risperidone. Antagonism at muscarinic receptors, H1-receptors, and alpha(1)-receptors also occurs with thiethylperazine. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 60% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Thiethylperazine is eliminated in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Manifestations of acute overdosage of TORECAN (thiethylperazine) can be expected to reflect the CNS effects of the drug and include extrapyramidal symptoms (E.P.S), confusion and convulsions with reduced or absent reflexes, respiratory depression and hypotension. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Norzine Thiethylperazin Thiéthylpérazine Thiethylperazine Thiethylperazinum Tietilperazina •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thiethylperazine is a drug used for the treatment of nausea and vomiting.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Thiethylperazine interact? Information: •Drug A: Bupropion •Drug B: Thiethylperazine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Thiethylperazine is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment or relief of nausea and vomiting. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Thiethylperazine, an atypical antipsychotic agent, is used to treat both negative and positive symptoms of schizophrenia, acute mania with bipolar disorder, agitation, and psychotic symptoms in dementia. Future uses may include the treatment of obsessive-compulsive disorder and severe behavioral disorders in autism. Structurally and pharmacologically similar to clozapine, Thiethylperazine binds to alpha(1), dopamine, histamine H1, muscarinic, and serotonin type 2 (5-HT2) receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Thiethylperazine is an antagonist at types 1, 2, and 4 dopamine receptors, 5-HT receptor types 2A and 2C, muscarinic receptors 1 through 5, alpha(1)-receptors, and histamine H1-receptors. Thiethylperazine's antipsychotic effect is due to antagonism at dopamine and serotonin type 2 receptors, with greater activity at serotonin 5-HT2 receptors than at dopamine type-2 receptors. This may explain the lack of extrapyramidal effects. Thiethylperazine does not appear to block dopamine within the tubero-infundibular tract, explaining the lower incidence of hyperprolactinemia than with typical antipsychotic agents or risperidone. Antagonism at muscarinic receptors, H1-receptors, and alpha(1)-receptors also occurs with thiethylperazine. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 60% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Thiethylperazine is eliminated in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Manifestations of acute overdosage of TORECAN (thiethylperazine) can be expected to reflect the CNS effects of the drug and include extrapyramidal symptoms (E.P.S), confusion and convulsions with reduced or absent reflexes, respiratory depression and hypotension. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Norzine Thiethylperazin Thiéthylpérazine Thiethylperazine Thiethylperazinum Tietilperazina •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thiethylperazine is a drug used for the treatment of nausea and vomiting. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Thiopental interact?

•Drug A: Bupropion •Drug B: Thiopental •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Thiopental is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For use as the sole anesthetic agent for brief (15 minute) procedures, for induction of anesthesia prior to administration of other anesthetic agents, to supplement regional anesthesia, to provide hypnosis during balanced anesthesia with other agents for analgesia or muscle relaxation, for the control of convulsive states during or following inhalation anesthesia or local anesthesia, in neurosurgical patients with increased intracranial pressure, and for narcoanalysis and narcosynthesis in psychiatric disorders. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Thiopental, a barbiturate, is used for the induction of anesthesia prior to the use of other general anesthetic agents and for induction of anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. Thiopental is an ultrashort-acting depressant of the central nervous system which induces hypnosis and anesthesia, but not analgesia. It produces hypnosis within 30 to 40 seconds of intravenous injection. Recovery after a small dose is rapid, with some somnolence and retrograde amnesia. Repeated intravenous doses lead to prolonged anesthesia because fatty tissues act as a reservoir; they accumulate Pentothal in concentrations 6 to 12 times greater than the plasma concentration, and then release the drug slowly to cause prolonged anesthesia •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Thiopental binds at a distinct binding site associated with a Cl ionopore at the GABA A receptor, increasing the duration of time for which the Cl ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 80% of the drug in the blood is bound to plasma protein. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Thiopental is extensively metabolized, primarily in the liver, resulting in only 0.3% of an administered dose being excreted unchanged in the urine. Ring desulfuration leads to the generation of an active metabolite, pentobarbital, that exists in concentrations approximately 3-10% that of the parent concentration. Thiopental and pentobarbital are also subject to both oxidation and hydroxylation to carboxylic acids and alcohols, respectively, all of which are pharmacologically inert. While many of the specifics regarding thiopental biotransformation have not been elucidated, including the enzymes responsible, the oxidation of thiopental to its carboxylic acid may be the major driver of thiopental detoxification as this product appears to account for 10-25% of renally excreted drug. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 3-8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Overdosage may occur from rapid or repeated injections. Too rapid injection may be followed by an alarming fall in blood pressure even to shock levels. Apnea, occasional laryngospasm, coughing and other respiratory difficulties with excessive or too rapid injections may occur. Lethal blood levels may be as low as 1 mg/100 mL for short-acting barbiturates; less if other depressant drugs or alcohol are also present. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Penthiobarbital Pentothiobarbital Thiopental Thiopentobarbital Thiopentobarbitone Thiopentobarbituric acid Thiopentone Tiopentale •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thiopental is a barbiturate used to induce general anesthesia, treat convulsions, and reduce intracranial pressure.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Thiopental interact? Information: •Drug A: Bupropion •Drug B: Thiopental •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Thiopental is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For use as the sole anesthetic agent for brief (15 minute) procedures, for induction of anesthesia prior to administration of other anesthetic agents, to supplement regional anesthesia, to provide hypnosis during balanced anesthesia with other agents for analgesia or muscle relaxation, for the control of convulsive states during or following inhalation anesthesia or local anesthesia, in neurosurgical patients with increased intracranial pressure, and for narcoanalysis and narcosynthesis in psychiatric disorders. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Thiopental, a barbiturate, is used for the induction of anesthesia prior to the use of other general anesthetic agents and for induction of anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. Thiopental is an ultrashort-acting depressant of the central nervous system which induces hypnosis and anesthesia, but not analgesia. It produces hypnosis within 30 to 40 seconds of intravenous injection. Recovery after a small dose is rapid, with some somnolence and retrograde amnesia. Repeated intravenous doses lead to prolonged anesthesia because fatty tissues act as a reservoir; they accumulate Pentothal in concentrations 6 to 12 times greater than the plasma concentration, and then release the drug slowly to cause prolonged anesthesia •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Thiopental binds at a distinct binding site associated with a Cl ionopore at the GABA A receptor, increasing the duration of time for which the Cl ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 80% of the drug in the blood is bound to plasma protein. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Thiopental is extensively metabolized, primarily in the liver, resulting in only 0.3% of an administered dose being excreted unchanged in the urine. Ring desulfuration leads to the generation of an active metabolite, pentobarbital, that exists in concentrations approximately 3-10% that of the parent concentration. Thiopental and pentobarbital are also subject to both oxidation and hydroxylation to carboxylic acids and alcohols, respectively, all of which are pharmacologically inert. While many of the specifics regarding thiopental biotransformation have not been elucidated, including the enzymes responsible, the oxidation of thiopental to its carboxylic acid may be the major driver of thiopental detoxification as this product appears to account for 10-25% of renally excreted drug. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 3-8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Overdosage may occur from rapid or repeated injections. Too rapid injection may be followed by an alarming fall in blood pressure even to shock levels. Apnea, occasional laryngospasm, coughing and other respiratory difficulties with excessive or too rapid injections may occur. Lethal blood levels may be as low as 1 mg/100 mL for short-acting barbiturates; less if other depressant drugs or alcohol are also present. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Penthiobarbital Pentothiobarbital Thiopental Thiopentobarbital Thiopentobarbitone Thiopentobarbituric acid Thiopentone Tiopentale •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thiopental is a barbiturate used to induce general anesthesia, treat convulsions, and reduce intracranial pressure. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Thioridazine interact?

•Drug A: Bupropion •Drug B: Thioridazine •Severity: MAJOR •Description: The metabolism of Thioridazine can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of schizophrenia and generalized anxiety disorder. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Thioridazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Thioridazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Thioridazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; blocks alpha-adrenergic effect, depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): 60% •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 95% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 21-25 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD 50 =956-1034 mg/kg (Orally in rats); Agitation, blurred vision, coma, confusion, constipation, difficulty breathing, dilated or constricted pupils, diminished flow of urine, dry mouth, dry skin, excessively high or low body temperature, extremely low blood pressure, fluid in the lungs, heart abnormalities, inability to urinate, intestinal blockage, nasal congestion, restlessness, sedation, seizures, shock •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Thioridazin Thioridazine Thioridazinum Tioridazina •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thioridazine is a phenothiazine antipsychotic used to treat schizophrenia and generalized anxiety disorder.

The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Thioridazine interact? Information: •Drug A: Bupropion •Drug B: Thioridazine •Severity: MAJOR •Description: The metabolism of Thioridazine can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of schizophrenia and generalized anxiety disorder. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Thioridazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Thioridazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Thioridazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; blocks alpha-adrenergic effect, depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): 60% •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 95% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 21-25 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD 50 =956-1034 mg/kg (Orally in rats); Agitation, blurred vision, coma, confusion, constipation, difficulty breathing, dilated or constricted pupils, diminished flow of urine, dry mouth, dry skin, excessively high or low body temperature, extremely low blood pressure, fluid in the lungs, heart abnormalities, inability to urinate, intestinal blockage, nasal congestion, restlessness, sedation, seizures, shock •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Thioridazin Thioridazine Thioridazinum Tioridazina •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thioridazine is a phenothiazine antipsychotic used to treat schizophrenia and generalized anxiety disorder. Output: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Thiosulfuric acid interact?

•Drug A: Bupropion •Drug B: Thiosulfuric acid •Severity: MODERATE •Description: The metabolism of Bupropion can be increased when combined with Thiosulfuric acid. •Extended Description: When a CYP2B6 substrate is administered concurrently with a CYP2B6 inducer of unknown strength, the CYP2B6 mediated metabolism of the substrate will subsequently be enhanced - either slightly, moderately, or greatly. Such increases in metabolism consequently result in decreases in the substrate's serum concentration and/or therapeutic effect. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Thiosulfuric acid (as sodium thiosulfate) is indicated for sequential intravenous use with sodium nitrite for the treatment of acute cyanide poisoning that is judged to be life-threatening. Sodium thiosulfate is also indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumors in the US. In Europe, it is indicated for the same prevention of ototoxicity for patients 1 month of age to < 18 years old. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Sodium thiosulfate doses of 20, 15 and 10 g/m deliver sodium loads of 162, 121 and 81 mmol/m. One hour after infusion, the administration of sodium thiosulfate causes a transient increase in sodium of approximately 6 mmol/L; however, levels return to baseline 18 to 24 hours after infusion. The pharmacodynamics of sodium thiosulfate as an antidote for the treatment of acute cyanide poisoning were evaluated by measuring the rate of conversion of cyanide to thiocyanate. Pretreatment with sodium thiosulfate to achieve a steady state level of 2 µmol/mL increased the rate of conversion of cyanide to thiocyanate over 30-fold in dogs. The use of sodium thiosulfate may cause hypersensitivity reactions and lead to hypernatremia and hypokalemia. It may also lead to nausea and vomiting. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): When administered with sodium nitrate, sodium thiosulfate acts as an antidote for the treatment of acute cyanide poisoning. Cyanide has a high affinity for cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. By binding and inhibiting cytochrome a3, cyanide prevents cells from using oxygen and forces anaerobic metabolism, inhibiting cellular respiration and resulting in lactic acidosis and cytotoxic hypoxia. Sodium nitrite reacts with hemoglobin to form methemoglobin, which competes with cytochrome a3 for the cyanide ion. Cyanide binds to methemoglobin to form cyanmethemoglobin, a nontoxic compound, and restore cytochrome oxidase activity. When cyanide dissociates from methemoglobin, sodium thiosulfate acts as a sulfur donor for the endogenous sulfur transferase enzyme and facilitates its conversion to thiocyanate, a less toxic ion. Sodium thiosulfate can also reduce the risk of ototoxicity associated with cisplatin. Pediatric patients treated with cisplatin have a high risk of developing ototoxicity, possibly due to a combination of reactive oxygen species (ROS) production and direct alkylation of DNA that leads to cell death. Sodium thiosulfate interacts with cisplatin to form inactive platinum species. It can also enter cells via the sodium sulfate cotransporter 2 to increase antioxidant glutathione levels and inhibit intracellular oxidative stress. Although a mechanism of action has not been fully elucidated, both activities are thought to reduce the risk of ototoxicity. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Sodium thiosulfate taken orally is not systemically absorbed. Most of the thiosulfate is oxidized to sulfate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys. In pediatric patients given the recommended intravenous dose of sodium thiosulfate, the C max of thiosulfate was 13 ± 1.2 mM, and increased proportionally to dose over the range of 4 g/m to 20 g/m. Thiosulfate accumulation is not expected following the intravenous administration of sodium thiosulfate on 2 consecutive days. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Thiosulfate has a mean volume of distribution of 0.23 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Sodium thiosulfate does not bind to human plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Thiosulfate sulfur transferase and thiosulfate reductase metabolize thiosulfate to form sulfite, which is oxidized to sulfate. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 20-50% of exogenously administered sodium thiosulfate is eliminated by the kidneys. More than 95% of the thiosulfate eliminated in urine is excreted within the first 4 hours after administration. When used as an antidote to cyanide poisoning, sodium thiosulfate is eliminated as thiocyanate, a relatively nontoxic compound. Thiocyanate is also excreted in urine at a rate inversely proportional to creatinine clearance. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half-life of thiosulfate administered intravenously (1 g sodium thiosulfate) was approximately 20 minutes. However, higher doses may increase this value. In healthy men given 150 mg/kg of sodium thiosulfate, the elimination half-life was 182 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): In patients with fully developed renal function (1 year old approximately), the mean total clearance of thiosulfate is 2.2 mL/min/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The effects in humans of large doses of sodium thiosulfate have not been thoroughly studied. Sodium thiosulfate administered orally (3 g per day) for 1-2 weeks resulted in reductions in room air arterial oxygen saturation to as low as 75%. One week after discontinuation, subjects returned to baseline oxygen saturations. A single dose of 20 mL of 10% sodium thiosulfate administered intravenously did not have an effect on oxygen saturation. In rats, the oral LD 50 of sodium thiosulfate pentahydrate is 5000 mg/kg.[L43327] The carcinogenic activity of sodium thiosulfate has not been evaluated. An in vitro bacterial reverse mutation assay showed that sodium thiosulfate was not mutagenic in the absence nor presence of metabolic activation. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Nithiodote, Pedmark, Seacalphyx •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thiosulfuric acid is a sulfur donor used sequentially with sodium nitrite for the reversal of life-threatening acute cyanide poisoning. Also used to reduce the risk of ototoxicity associated with cisplatin.

When a CYP2B6 substrate is administered concurrently with a CYP2B6 inducer of unknown strength, the CYP2B6 mediated metabolism of the substrate will subsequently be enhanced - either slightly, moderately, or greatly. Such increases in metabolism consequently result in decreases in the substrate's serum concentration and/or therapeutic effect. The severity of the interaction is moderate.

Question: Does Bupropion and Thiosulfuric acid interact? Information: •Drug A: Bupropion •Drug B: Thiosulfuric acid •Severity: MODERATE •Description: The metabolism of Bupropion can be increased when combined with Thiosulfuric acid. •Extended Description: When a CYP2B6 substrate is administered concurrently with a CYP2B6 inducer of unknown strength, the CYP2B6 mediated metabolism of the substrate will subsequently be enhanced - either slightly, moderately, or greatly. Such increases in metabolism consequently result in decreases in the substrate's serum concentration and/or therapeutic effect. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Thiosulfuric acid (as sodium thiosulfate) is indicated for sequential intravenous use with sodium nitrite for the treatment of acute cyanide poisoning that is judged to be life-threatening. Sodium thiosulfate is also indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumors in the US. In Europe, it is indicated for the same prevention of ototoxicity for patients 1 month of age to < 18 years old. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Sodium thiosulfate doses of 20, 15 and 10 g/m deliver sodium loads of 162, 121 and 81 mmol/m. One hour after infusion, the administration of sodium thiosulfate causes a transient increase in sodium of approximately 6 mmol/L; however, levels return to baseline 18 to 24 hours after infusion. The pharmacodynamics of sodium thiosulfate as an antidote for the treatment of acute cyanide poisoning were evaluated by measuring the rate of conversion of cyanide to thiocyanate. Pretreatment with sodium thiosulfate to achieve a steady state level of 2 µmol/mL increased the rate of conversion of cyanide to thiocyanate over 30-fold in dogs. The use of sodium thiosulfate may cause hypersensitivity reactions and lead to hypernatremia and hypokalemia. It may also lead to nausea and vomiting. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): When administered with sodium nitrate, sodium thiosulfate acts as an antidote for the treatment of acute cyanide poisoning. Cyanide has a high affinity for cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. By binding and inhibiting cytochrome a3, cyanide prevents cells from using oxygen and forces anaerobic metabolism, inhibiting cellular respiration and resulting in lactic acidosis and cytotoxic hypoxia. Sodium nitrite reacts with hemoglobin to form methemoglobin, which competes with cytochrome a3 for the cyanide ion. Cyanide binds to methemoglobin to form cyanmethemoglobin, a nontoxic compound, and restore cytochrome oxidase activity. When cyanide dissociates from methemoglobin, sodium thiosulfate acts as a sulfur donor for the endogenous sulfur transferase enzyme and facilitates its conversion to thiocyanate, a less toxic ion. Sodium thiosulfate can also reduce the risk of ototoxicity associated with cisplatin. Pediatric patients treated with cisplatin have a high risk of developing ototoxicity, possibly due to a combination of reactive oxygen species (ROS) production and direct alkylation of DNA that leads to cell death. Sodium thiosulfate interacts with cisplatin to form inactive platinum species. It can also enter cells via the sodium sulfate cotransporter 2 to increase antioxidant glutathione levels and inhibit intracellular oxidative stress. Although a mechanism of action has not been fully elucidated, both activities are thought to reduce the risk of ototoxicity. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Sodium thiosulfate taken orally is not systemically absorbed. Most of the thiosulfate is oxidized to sulfate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys. In pediatric patients given the recommended intravenous dose of sodium thiosulfate, the C max of thiosulfate was 13 ± 1.2 mM, and increased proportionally to dose over the range of 4 g/m to 20 g/m. Thiosulfate accumulation is not expected following the intravenous administration of sodium thiosulfate on 2 consecutive days. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Thiosulfate has a mean volume of distribution of 0.23 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Sodium thiosulfate does not bind to human plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Thiosulfate sulfur transferase and thiosulfate reductase metabolize thiosulfate to form sulfite, which is oxidized to sulfate. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 20-50% of exogenously administered sodium thiosulfate is eliminated by the kidneys. More than 95% of the thiosulfate eliminated in urine is excreted within the first 4 hours after administration. When used as an antidote to cyanide poisoning, sodium thiosulfate is eliminated as thiocyanate, a relatively nontoxic compound. Thiocyanate is also excreted in urine at a rate inversely proportional to creatinine clearance. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half-life of thiosulfate administered intravenously (1 g sodium thiosulfate) was approximately 20 minutes. However, higher doses may increase this value. In healthy men given 150 mg/kg of sodium thiosulfate, the elimination half-life was 182 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): In patients with fully developed renal function (1 year old approximately), the mean total clearance of thiosulfate is 2.2 mL/min/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The effects in humans of large doses of sodium thiosulfate have not been thoroughly studied. Sodium thiosulfate administered orally (3 g per day) for 1-2 weeks resulted in reductions in room air arterial oxygen saturation to as low as 75%. One week after discontinuation, subjects returned to baseline oxygen saturations. A single dose of 20 mL of 10% sodium thiosulfate administered intravenously did not have an effect on oxygen saturation. In rats, the oral LD 50 of sodium thiosulfate pentahydrate is 5000 mg/kg.[L43327] The carcinogenic activity of sodium thiosulfate has not been evaluated. An in vitro bacterial reverse mutation assay showed that sodium thiosulfate was not mutagenic in the absence nor presence of metabolic activation. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Nithiodote, Pedmark, Seacalphyx •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thiosulfuric acid is a sulfur donor used sequentially with sodium nitrite for the reversal of life-threatening acute cyanide poisoning. Also used to reduce the risk of ototoxicity associated with cisplatin. Output: When a CYP2B6 substrate is administered concurrently with a CYP2B6 inducer of unknown strength, the CYP2B6 mediated metabolism of the substrate will subsequently be enhanced - either slightly, moderately, or greatly. Such increases in metabolism consequently result in decreases in the substrate's serum concentration and/or therapeutic effect. The severity of the interaction is moderate.

Does Bupropion and Thiotepa interact?

•Drug A: Bupropion •Drug B: Thiotepa •Severity: MINOR •Description: The serum concentration of Bupropion can be increased when it is combined with Thiotepa. •Extended Description: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): ThioTEPA is used a as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients. Also, when high dose chemotherapy with HPCT support it is appropriate for the treatment of solid tumours in adult and paediatric patients. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): The unstable nitrogen-carbon groups alkylate with DNA causing irrepairable DNA damage. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Urinary excretion of 14C-labeled thiotepa and metabolites in a 34-year old patient with metastatic carcinoma of the cecum who received a dose of 0.3 mg/kg intravenously was 63%. •Half-life (Drug A): 24 hours •Half-life (Drug B): 1.5 to 4.1 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 446 +/- 63 mL/min [female patients (45 to 84 years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by intravenous infusion on subsequent courses given at 4-week intervals] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tepadina •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thiotepa is an alkylating agent used to prevent graft rejection in stem cell transplantation and to treat a variety of malignancies including certain types of adenocarcinoma and superficial bladder carcinomas.

Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. The severity of the interaction is minor.

Question: Does Bupropion and Thiotepa interact? Information: •Drug A: Bupropion •Drug B: Thiotepa •Severity: MINOR •Description: The serum concentration of Bupropion can be increased when it is combined with Thiotepa. •Extended Description: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): ThioTEPA is used a as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients. Also, when high dose chemotherapy with HPCT support it is appropriate for the treatment of solid tumours in adult and paediatric patients. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): The unstable nitrogen-carbon groups alkylate with DNA causing irrepairable DNA damage. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Urinary excretion of 14C-labeled thiotepa and metabolites in a 34-year old patient with metastatic carcinoma of the cecum who received a dose of 0.3 mg/kg intravenously was 63%. •Half-life (Drug A): 24 hours •Half-life (Drug B): 1.5 to 4.1 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 446 +/- 63 mL/min [female patients (45 to 84 years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by intravenous infusion on subsequent courses given at 4-week intervals] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tepadina •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thiotepa is an alkylating agent used to prevent graft rejection in stem cell transplantation and to treat a variety of malignancies including certain types of adenocarcinoma and superficial bladder carcinomas. Output: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. The severity of the interaction is minor.

Does Bupropion and Thiothixene interact?

•Drug A: Bupropion •Drug B: Thiothixene •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Bupropion is combined with Thiothixene. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the management of schizophrenia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Thiothixene is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. Although widely used in the treatment of schizophrenia for several decades, thiothixene is seldom used today in favor of atypical antipsychotics such as risperidone. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Thiothixene acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 10-20 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include central nervous system depression, coma, difficulty swallowing, dizziness, drowsiness, head tilted to the side, low blood pressure, muscle twitching, rigid muscles, salivation, tremors, walking disturbances, and weakness. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Navane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thiothixene is an antipsychotic indicated for the management of schizophrenia.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Thiothixene interact? Information: •Drug A: Bupropion •Drug B: Thiothixene •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Bupropion is combined with Thiothixene. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the management of schizophrenia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Thiothixene is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. Although widely used in the treatment of schizophrenia for several decades, thiothixene is seldom used today in favor of atypical antipsychotics such as risperidone. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Thiothixene acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 10-20 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include central nervous system depression, coma, difficulty swallowing, dizziness, drowsiness, head tilted to the side, low blood pressure, muscle twitching, rigid muscles, salivation, tremors, walking disturbances, and weakness. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Navane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Thiothixene is an antipsychotic indicated for the management of schizophrenia. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Tiagabine interact?

•Drug A: Bupropion •Drug B: Tiagabine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Tiagabine is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of partial seizures •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tiagabine is used primarily as an anticonvulsant for the adjunctive treatment of epilepsy. The precise mechanism by which Tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that, by this action, Tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Though the exact mechanism by which Tiagabine exerts its effect on the human body is unknown, it does appear to operate as a selective GABA reuptake inhibitor. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Tiagabine is nearly completely absorbed (>95%). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 96% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tiagabine is likely metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites. •Half-life (Drug A): 24 hours •Half-life (Drug B): 7-9 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 109 mL/min [Healthy subjects] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): mptoms most often accompanying tiagabine overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, coma, ataxia, confusion, somnolence, drowsiness, impaired speech, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Gabitril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tiagabine is an antiepileptic used to treat partial seizures.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Tiagabine interact? Information: •Drug A: Bupropion •Drug B: Tiagabine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Tiagabine is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of partial seizures •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tiagabine is used primarily as an anticonvulsant for the adjunctive treatment of epilepsy. The precise mechanism by which Tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that, by this action, Tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Though the exact mechanism by which Tiagabine exerts its effect on the human body is unknown, it does appear to operate as a selective GABA reuptake inhibitor. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Tiagabine is nearly completely absorbed (>95%). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 96% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tiagabine is likely metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites. •Half-life (Drug A): 24 hours •Half-life (Drug B): 7-9 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 109 mL/min [Healthy subjects] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): mptoms most often accompanying tiagabine overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, coma, ataxia, confusion, somnolence, drowsiness, impaired speech, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Gabitril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tiagabine is an antiepileptic used to treat partial seizures. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Tiaprofenic acid interact?

•Drug A: Bupropion •Drug B: Tiaprofenic acid •Severity: MINOR •Description: Tiaprofenic acid may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tiaprofenic acid is used to treat pain, especially arthritic pain. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tiaprofenic acid is a non-steroidal anti-inflammatory drug of the arylpropionic acid (profen) class, used to treat pain, especially arthritic pain. The typical adult dose is 300mg twice daily. This drug is not recommended for use in the pediatric population. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tiaprofenic acid belongs to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). It works by blocking the production of a chemical (prostaglandin) which the body produces in response to injury or certain diseases. This prostaglandin would otherwise go on to cause swelling, pain and inflammation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Bioavailability is 90% following oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic (10%). Sparingly metabolised in the liver to two inactive metabolites. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 1.5-2.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide tiaprofenique Acido tiaprofenico Acidum tiaprofenicum Tiaprofenic acid Tiaprofensäure •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tiaprofenic acid is a nonsteroidal anti-inflammatory (NSAID) used to manage inflammation and analgesia associated with rheumatoid arthritis and osteoarthritis.

The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Tiaprofenic acid interact? Information: •Drug A: Bupropion •Drug B: Tiaprofenic acid •Severity: MINOR •Description: Tiaprofenic acid may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tiaprofenic acid is used to treat pain, especially arthritic pain. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tiaprofenic acid is a non-steroidal anti-inflammatory drug of the arylpropionic acid (profen) class, used to treat pain, especially arthritic pain. The typical adult dose is 300mg twice daily. This drug is not recommended for use in the pediatric population. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tiaprofenic acid belongs to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). It works by blocking the production of a chemical (prostaglandin) which the body produces in response to injury or certain diseases. This prostaglandin would otherwise go on to cause swelling, pain and inflammation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Bioavailability is 90% following oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic (10%). Sparingly metabolised in the liver to two inactive metabolites. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 1.5-2.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide tiaprofenique Acido tiaprofenico Acidum tiaprofenicum Tiaprofenic acid Tiaprofensäure •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tiaprofenic acid is a nonsteroidal anti-inflammatory (NSAID) used to manage inflammation and analgesia associated with rheumatoid arthritis and osteoarthritis. Output: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Does Bupropion and Ticagrelor interact?

•Drug A: Bupropion •Drug B: Ticagrelor •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Ticagrelor. •Extended Description: The subject drug is known to be a weak inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Ticagrelor is indicated to reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor is also indicated to reduce the risk of a first myocardial infarction or stroke in high risk patients with coronary artery disease. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Ticagrelor is a P2Y 12 receptor antagonist that inhibits the formation of thromboses to reduce the risk of myocardial infarction and ischemic stroke. It has a moderate duration of action as it is given twice daily, and a wide therapeutic index as high single doses are well tolerated. Patients should be counselled regarding the risk of bleeding, dyspnea, and bradyarrhythmias. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Ticagrelor is a P2Y 12 receptor antagonist. The P2Y 12 receptor couples with Gα i2 and other G i proteins which inhibit adenylyl cyclase. G i mediated signalling also activates PI3K, Akt, Rap1b, and potassium channels. The downstream effects of these activities mediate hemostasis and lead to platelet aggregation. Antagonism of the P2Y 12 receptor reduces development of occlusive thromboses, which can reduce the risk of myocardial infarction and ischemic stroke. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Ticagrelor is 36% orally bioavailable. A single 200mg oral dose of ticagrelor reaches a C max of 923ng/mL, with a T max of 1.5 hours and an AUC of 6675ng*h/mL. The active metabolite of ticagrelor reaches a C max of 264ng/mL, with a T max of 3.0 hours and an AUC of 2538ng*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The steady state volume of distribution of ticagrelor is 88 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Ticagrelor and its active metabolite ate >99% protein bound in plasma, particularly albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The complete structure of all ticagrelor metabolites are not well defined. Ticagrelor can be dealkylated at postition 5 of the cyclopentane ring to form the active AR-C124910XX. AR-C124910XX's cyclopentane ring can be further glucuronidated or the alkyl chain attached to the sulfur can be hydroxylated. Ticagrelor can also be glucuronidated or hydroxylated. Ticagrelor can also be N-dealkylated to form AR-C133913XX, which is further glucuronidated or hydroxylated. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): A radiolabelled dose of ticagrelor is 57.8% recovered in feces and 26.5% recovered in urine. Less than 1% of the dose is recovered as the unmetabolized parent drug. The active metabolite AC-C124910XX makes up 21.7% of the recovery in the feces. The metabolite AR-C133913XX makes up 9.2% of the recovery in the urine and 2.7% of the recovery in the feces. Other minor metabolites are predominantly recovered in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Ticagrelor has a plasma half life of approximately 8 hours, while the active metabolite has a plasma half life of approximately 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The renal clearance of ticagrelor is 0.00584L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Patients experiencing an overdose may present with bleeding, nausea, vomiting, diarrhea, and ventricular pauses. Overdose can be managed through symptomatic and supportive treatment, including ECG monitoring. Dialysis is not expected to remove ticagrelor from the blood due to it being highly protein bound. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Brilinta, Brilique •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ticagrelor •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Ticagrelor is a P2Y12 platelet inhibitor used in patients with a history of myocardial infarction or with acute coronary syndrome (ACS) to prevent future myocardial infarction, stroke and cardiovascular death.

The subject drug is known to be a weak inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is minor.

Question: Does Bupropion and Ticagrelor interact? Information: •Drug A: Bupropion •Drug B: Ticagrelor •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Ticagrelor. •Extended Description: The subject drug is known to be a weak inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Ticagrelor is indicated to reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor is also indicated to reduce the risk of a first myocardial infarction or stroke in high risk patients with coronary artery disease. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Ticagrelor is a P2Y 12 receptor antagonist that inhibits the formation of thromboses to reduce the risk of myocardial infarction and ischemic stroke. It has a moderate duration of action as it is given twice daily, and a wide therapeutic index as high single doses are well tolerated. Patients should be counselled regarding the risk of bleeding, dyspnea, and bradyarrhythmias. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Ticagrelor is a P2Y 12 receptor antagonist. The P2Y 12 receptor couples with Gα i2 and other G i proteins which inhibit adenylyl cyclase. G i mediated signalling also activates PI3K, Akt, Rap1b, and potassium channels. The downstream effects of these activities mediate hemostasis and lead to platelet aggregation. Antagonism of the P2Y 12 receptor reduces development of occlusive thromboses, which can reduce the risk of myocardial infarction and ischemic stroke. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Ticagrelor is 36% orally bioavailable. A single 200mg oral dose of ticagrelor reaches a C max of 923ng/mL, with a T max of 1.5 hours and an AUC of 6675ng*h/mL. The active metabolite of ticagrelor reaches a C max of 264ng/mL, with a T max of 3.0 hours and an AUC of 2538ng*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The steady state volume of distribution of ticagrelor is 88 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Ticagrelor and its active metabolite ate >99% protein bound in plasma, particularly albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The complete structure of all ticagrelor metabolites are not well defined. Ticagrelor can be dealkylated at postition 5 of the cyclopentane ring to form the active AR-C124910XX. AR-C124910XX's cyclopentane ring can be further glucuronidated or the alkyl chain attached to the sulfur can be hydroxylated. Ticagrelor can also be glucuronidated or hydroxylated. Ticagrelor can also be N-dealkylated to form AR-C133913XX, which is further glucuronidated or hydroxylated. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): A radiolabelled dose of ticagrelor is 57.8% recovered in feces and 26.5% recovered in urine. Less than 1% of the dose is recovered as the unmetabolized parent drug. The active metabolite AC-C124910XX makes up 21.7% of the recovery in the feces. The metabolite AR-C133913XX makes up 9.2% of the recovery in the urine and 2.7% of the recovery in the feces. Other minor metabolites are predominantly recovered in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Ticagrelor has a plasma half life of approximately 8 hours, while the active metabolite has a plasma half life of approximately 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The renal clearance of ticagrelor is 0.00584L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Patients experiencing an overdose may present with bleeding, nausea, vomiting, diarrhea, and ventricular pauses. Overdose can be managed through symptomatic and supportive treatment, including ECG monitoring. Dialysis is not expected to remove ticagrelor from the blood due to it being highly protein bound. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Brilinta, Brilique •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ticagrelor •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Ticagrelor is a P2Y12 platelet inhibitor used in patients with a history of myocardial infarction or with acute coronary syndrome (ACS) to prevent future myocardial infarction, stroke and cardiovascular death. Output: The subject drug is known to be a weak inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is minor.

Does Bupropion and Ticlopidine interact?

•Drug A: Bupropion •Drug B: Ticlopidine •Severity: MODERATE •Description: The metabolism of Bupropion can be decreased when combined with Ticlopidine. •Extended Description: Prescribing information for extended-release bupropion (Wellbutrin® XL) states that its concomitant use with ticlopidine may cause an increase in bupropion exposure and a subsequent decrease in hydroxybupropion (an active bupropion metabolite) exposure. Ticlopidine is known to inhibit CYP2B6, which is the main enzyme involved in the hydroxylation of bupropion to hydroxybupropion - its coadministration with bupropion resulted in an 84% reduction in hydroxybupropion AUC, and an increase in parent drug AUC and Cmax of 73% and 39%, respectively. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Used in patients, who have had a stroke or stroke precursors and who cannot take aspirin or aspirin has not worked, to try to prevent another thrombotic stroke. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Ticlopidine is a prodrug that is metabolised to an as yet undetermined metabolite that acts as a platelet aggregation inhibitor. Inhibition of platelet aggregation causes a prolongation of bleeding time. In its prodrug form, ticlopidine has no significant in vitro activity at the concentrations attained in vivo. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The active metabolite of ticlopidine prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of ticlopidine. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Absorption is greater than 80%. Food increases absorption by approximately 20%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution was not quantified. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein (about 15% or less). •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Ticlopidine is metabolized extensively by the liver with only trace amounts of intact drug detected. At least 20 metabolites have been identified. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Ticlopidine is eliminated mostly in the urine (60%) and somewhat in the feces (23%). •Half-life (Drug A): 24 hours •Half-life (Drug B): Half-life following a single 250-mg dose is approximately 7.9 hours in subjects 20 to 43 years of age and 12.6 hours in subjects 65 to 76 years of age. With repeated dosing (250 mg twice a day), half-life is about 4 days in subjects 20 to 43 years of age and about 5 days in subjects 65 to 76 years of age. •Clearance (Drug A): No clearance available •Clearance (Drug B): Ticlopidine clearance was not quantified, but clearance decreases with age. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were GI hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait. The FDA label includes a black-box warning of neutropenia, aplastic anemia, thrombotic thrombocytopenia purpura, and agranulocytosis, so it is necessary to monitor patients' WBC and platelets when they are taking ticlopidine. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Ticlopidine is a platelet aggregation inhibitor used in the prevention of conditions associated with thrombi, such as stroke and transient ischemic attacks (TIA).

Prescribing information for extended-release bupropion (Wellbutrin® XL) states that its concomitant use with ticlopidine may cause an increase in bupropion exposure and a subsequent decrease in hydroxybupropion (an active bupropion metabolite) exposure. Ticlopidine is known to inhibit CYP2B6, which is the main enzyme involved in the hydroxylation of bupropion to hydroxybupropion - its coadministration with bupropion resulted in an 84% reduction in hydroxybupropion AUC, and an increase in parent drug AUC and Cmax of 73% and 39%, respectively. The severity of the interaction is moderate.

Question: Does Bupropion and Ticlopidine interact? Information: •Drug A: Bupropion •Drug B: Ticlopidine •Severity: MODERATE •Description: The metabolism of Bupropion can be decreased when combined with Ticlopidine. •Extended Description: Prescribing information for extended-release bupropion (Wellbutrin® XL) states that its concomitant use with ticlopidine may cause an increase in bupropion exposure and a subsequent decrease in hydroxybupropion (an active bupropion metabolite) exposure. Ticlopidine is known to inhibit CYP2B6, which is the main enzyme involved in the hydroxylation of bupropion to hydroxybupropion - its coadministration with bupropion resulted in an 84% reduction in hydroxybupropion AUC, and an increase in parent drug AUC and Cmax of 73% and 39%, respectively. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Used in patients, who have had a stroke or stroke precursors and who cannot take aspirin or aspirin has not worked, to try to prevent another thrombotic stroke. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Ticlopidine is a prodrug that is metabolised to an as yet undetermined metabolite that acts as a platelet aggregation inhibitor. Inhibition of platelet aggregation causes a prolongation of bleeding time. In its prodrug form, ticlopidine has no significant in vitro activity at the concentrations attained in vivo. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The active metabolite of ticlopidine prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of ticlopidine. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Absorption is greater than 80%. Food increases absorption by approximately 20%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution was not quantified. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein (about 15% or less). •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Ticlopidine is metabolized extensively by the liver with only trace amounts of intact drug detected. At least 20 metabolites have been identified. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Ticlopidine is eliminated mostly in the urine (60%) and somewhat in the feces (23%). •Half-life (Drug A): 24 hours •Half-life (Drug B): Half-life following a single 250-mg dose is approximately 7.9 hours in subjects 20 to 43 years of age and 12.6 hours in subjects 65 to 76 years of age. With repeated dosing (250 mg twice a day), half-life is about 4 days in subjects 20 to 43 years of age and about 5 days in subjects 65 to 76 years of age. •Clearance (Drug A): No clearance available •Clearance (Drug B): Ticlopidine clearance was not quantified, but clearance decreases with age. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were GI hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait. The FDA label includes a black-box warning of neutropenia, aplastic anemia, thrombotic thrombocytopenia purpura, and agranulocytosis, so it is necessary to monitor patients' WBC and platelets when they are taking ticlopidine. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Ticlopidine is a platelet aggregation inhibitor used in the prevention of conditions associated with thrombi, such as stroke and transient ischemic attacks (TIA). Output: Prescribing information for extended-release bupropion (Wellbutrin® XL) states that its concomitant use with ticlopidine may cause an increase in bupropion exposure and a subsequent decrease in hydroxybupropion (an active bupropion metabolite) exposure. Ticlopidine is known to inhibit CYP2B6, which is the main enzyme involved in the hydroxylation of bupropion to hydroxybupropion - its coadministration with bupropion resulted in an 84% reduction in hydroxybupropion AUC, and an increase in parent drug AUC and Cmax of 73% and 39%, respectively. The severity of the interaction is moderate.

Does Bupropion and Timolol interact?

•Drug A: Bupropion •Drug B: Timolol •Severity: MODERATE •Description: The metabolism of Timolol can be decreased when combined with Bupropion. •Extended Description: Timolol relies on CYP2D6 enzyme for metabolism. Inhibitors of this enzyme are likely to lead to decreased metabolism and increased exposure to timolol, leading to bradycardia and other adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Ophthalmic timolol is indicated for the treatment of increased intraocular pressure in patients with ocular hypertension or open-angle glaucoma. The oral form of this drug is used to treat high blood pressure. In certain cases, timolol is used in the prevention of migraine headaches. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Timolol, when administered by the ophthalmic route, rapidly reduces intraocular pressure. When administered in the tablet form, it reduces blood pressure, heart rate, and cardiac output, and decreases sympathetic activity.. This drug has a fast onset of action, usually occurring within 20 minutes of the administration of an ophthalmic dose. Timolol maleate can exert pharmacological actions for as long as 24 hours if given in the 0.5% or 0.25% doses. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure. The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye. According to one study, the reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 ± 24.5%, indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers. The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 1.3 - 1.7 L/kg Timolol is distributed to the following tissues: the conjunctiva, cornea, iris, sclera, aqueous humor, kidney, liver, and lung. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The plasma protein binding of timolol is not extensive and is estimated to be about 10%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Timolol is metabolized in the liver by the cytochrome P450 2D6 enzyme, with minor contributions from CYP2C19. 15-20% of a dose undergoes first-pass metabolism. Despite its relatively low first pass metabolism, timolol is 90% metabolized. Four metabolites of timolol have been identified, with a hydroxy metabolite being the most predominant. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Timolol and its metabolites are mainly found excreted in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Timolol half-life was measured at 2.9 ± 0.3 h hours in a clinical study of healthy volunteers. •Clearance (Drug A): No clearance available •Clearance (Drug B): One pharmacokinetic study in healthy volunteers measured the total plasma clearance of timolol to be 557 ± 61 ml/min. Another study determined the total clearance 751.5 ± 90.6 ml/min and renal clearance to be 97.2 ± 10.1 ml/min in healthy volunteers. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD50 for timolol maleate is 1028 mg/kg in the rat and 1137 mg/kg in the mouse. Symptoms of timolol overdose may include dizziness, headache, shortness of breath, bradycardia, in addition to bronchospasm. Sometimes, an overdose may lead to cardiac arrest. An overdose of timolol can be reversed with dialysis, however, patients with renal failure may not respond as well to dialysis treatment. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Azarga, Betimol, Combigan, Cosopt, Duotrav, Istalol, Timoptic, Xalacom •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Timolol Timololo Timololum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Timolol is a non-selective beta adrenergic blocker used in the treatment of elevated intraocular pressure in ocular hypertension or open angle glaucoma.

Timolol relies on CYP2D6 enzyme for metabolism. Inhibitors of this enzyme are likely to lead to decreased metabolism and increased exposure to timolol, leading to bradycardia and other adverse effects. The severity of the interaction is moderate.

Question: Does Bupropion and Timolol interact? Information: •Drug A: Bupropion •Drug B: Timolol •Severity: MODERATE •Description: The metabolism of Timolol can be decreased when combined with Bupropion. •Extended Description: Timolol relies on CYP2D6 enzyme for metabolism. Inhibitors of this enzyme are likely to lead to decreased metabolism and increased exposure to timolol, leading to bradycardia and other adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Ophthalmic timolol is indicated for the treatment of increased intraocular pressure in patients with ocular hypertension or open-angle glaucoma. The oral form of this drug is used to treat high blood pressure. In certain cases, timolol is used in the prevention of migraine headaches. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Timolol, when administered by the ophthalmic route, rapidly reduces intraocular pressure. When administered in the tablet form, it reduces blood pressure, heart rate, and cardiac output, and decreases sympathetic activity.. This drug has a fast onset of action, usually occurring within 20 minutes of the administration of an ophthalmic dose. Timolol maleate can exert pharmacological actions for as long as 24 hours if given in the 0.5% or 0.25% doses. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure. The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye. According to one study, the reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 ± 24.5%, indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers. The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 1.3 - 1.7 L/kg Timolol is distributed to the following tissues: the conjunctiva, cornea, iris, sclera, aqueous humor, kidney, liver, and lung. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The plasma protein binding of timolol is not extensive and is estimated to be about 10%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Timolol is metabolized in the liver by the cytochrome P450 2D6 enzyme, with minor contributions from CYP2C19. 15-20% of a dose undergoes first-pass metabolism. Despite its relatively low first pass metabolism, timolol is 90% metabolized. Four metabolites of timolol have been identified, with a hydroxy metabolite being the most predominant. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Timolol and its metabolites are mainly found excreted in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Timolol half-life was measured at 2.9 ± 0.3 h hours in a clinical study of healthy volunteers. •Clearance (Drug A): No clearance available •Clearance (Drug B): One pharmacokinetic study in healthy volunteers measured the total plasma clearance of timolol to be 557 ± 61 ml/min. Another study determined the total clearance 751.5 ± 90.6 ml/min and renal clearance to be 97.2 ± 10.1 ml/min in healthy volunteers. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD50 for timolol maleate is 1028 mg/kg in the rat and 1137 mg/kg in the mouse. Symptoms of timolol overdose may include dizziness, headache, shortness of breath, bradycardia, in addition to bronchospasm. Sometimes, an overdose may lead to cardiac arrest. An overdose of timolol can be reversed with dialysis, however, patients with renal failure may not respond as well to dialysis treatment. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Azarga, Betimol, Combigan, Cosopt, Duotrav, Istalol, Timoptic, Xalacom •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Timolol Timololo Timololum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Timolol is a non-selective beta adrenergic blocker used in the treatment of elevated intraocular pressure in ocular hypertension or open angle glaucoma. Output: Timolol relies on CYP2D6 enzyme for metabolism. Inhibitors of this enzyme are likely to lead to decreased metabolism and increased exposure to timolol, leading to bradycardia and other adverse effects. The severity of the interaction is moderate.

Does Bupropion and Tinidazole interact?

•Drug A: Bupropion •Drug B: Tinidazole •Severity: MINOR •Description: Tinidazole may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of trichomoniasis caused by T. vaginalis in both female and male patients. Also for the treatment of giardiasis caused by G. duodenalis in both adults and pediatric patients older than three years of age and for the treatment of intestinal amebiasis and amebic liver abscess caused by E. histolytica in both adults and pediatric patients older than three years of age. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tinidazole is a synthetic antiprotozoal agent. Tinidazole demonstrates activity both in vitro and in clinical infections against the following protozoa: Trichomonas vaginalis, Giardia duodenalis (also termed G. lamblia ), and Entamoeba histolytica. Tinidazole does not appear to have activity against most strains of vaginal lactobacilli. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tinidazole is a prodrug and antiprotozoal agent. The nitro group of tinidazole is reduced in Trichomonas by a ferredoxin-mediated electron transport system. The free nitro radical generated as a result of this reduction is believed to be responsible for the antiprotozoal activity. It is suggested that the toxic free radicals covalently bind to DNA, causing DNA damage and leading to cell death. The mechanism by which tinidazole exhibits activity against Giardia and Entamoeba species is not known, though it is probably similar. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly and completely absorbed under fasting conditions. Administration with food results in a delay in T max of approximately 2 hours and a decline in C max of approximately 10% and an AUC of 901.6 ± 126.5 mcg hr/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 50 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Plasma protein binding of tinidazole is 12%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic, mainly via CYP3A4. Tinidazole, like metronidazole, is significantly metabolized in humans prior to excretion. Tinidazole is partly metabolized by oxidation, hydroxylation and conjugation. Tinidazole is the major drug-related constituent in plasma after human treatment, along with a small amount of the 2-hydroxymethyl metabolite. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tinidazole crosses the placental barrier and is secreted in breast milk. Tinidazole is excreted by the liver and the kidneys. Tinidazole is excreted in the urine mainly as unchanged drug (approximately 20-25% of the administered dose). Approximately 12% of the drug is excreted in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life is 13.2±1.4 hours and the plasma half-life is 12 to 14 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): There are no reported overdoses with tinidazole in humans. In acute studies with mice and rats, the LD 50 for mice was generally > 3,600 mg/kg for oral administration and was > 2,300 mg/kg for intraperitoneal administration. In rats, the LD 50 was > 2,000 mg/kg for both oral and intraperitoneal administration. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tindamax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Timidazole Tinidazol Tinidazole Tinidazolum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tinidazole is a nitroimidazole used to treat trichomoniasis, giardiasis, amebiasis, and bacterial vaginosis.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Tinidazole interact? Information: •Drug A: Bupropion •Drug B: Tinidazole •Severity: MINOR •Description: Tinidazole may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of trichomoniasis caused by T. vaginalis in both female and male patients. Also for the treatment of giardiasis caused by G. duodenalis in both adults and pediatric patients older than three years of age and for the treatment of intestinal amebiasis and amebic liver abscess caused by E. histolytica in both adults and pediatric patients older than three years of age. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tinidazole is a synthetic antiprotozoal agent. Tinidazole demonstrates activity both in vitro and in clinical infections against the following protozoa: Trichomonas vaginalis, Giardia duodenalis (also termed G. lamblia ), and Entamoeba histolytica. Tinidazole does not appear to have activity against most strains of vaginal lactobacilli. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tinidazole is a prodrug and antiprotozoal agent. The nitro group of tinidazole is reduced in Trichomonas by a ferredoxin-mediated electron transport system. The free nitro radical generated as a result of this reduction is believed to be responsible for the antiprotozoal activity. It is suggested that the toxic free radicals covalently bind to DNA, causing DNA damage and leading to cell death. The mechanism by which tinidazole exhibits activity against Giardia and Entamoeba species is not known, though it is probably similar. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly and completely absorbed under fasting conditions. Administration with food results in a delay in T max of approximately 2 hours and a decline in C max of approximately 10% and an AUC of 901.6 ± 126.5 mcg hr/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 50 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Plasma protein binding of tinidazole is 12%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic, mainly via CYP3A4. Tinidazole, like metronidazole, is significantly metabolized in humans prior to excretion. Tinidazole is partly metabolized by oxidation, hydroxylation and conjugation. Tinidazole is the major drug-related constituent in plasma after human treatment, along with a small amount of the 2-hydroxymethyl metabolite. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tinidazole crosses the placental barrier and is secreted in breast milk. Tinidazole is excreted by the liver and the kidneys. Tinidazole is excreted in the urine mainly as unchanged drug (approximately 20-25% of the administered dose). Approximately 12% of the drug is excreted in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life is 13.2±1.4 hours and the plasma half-life is 12 to 14 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): There are no reported overdoses with tinidazole in humans. In acute studies with mice and rats, the LD 50 for mice was generally > 3,600 mg/kg for oral administration and was > 2,300 mg/kg for intraperitoneal administration. In rats, the LD 50 was > 2,000 mg/kg for both oral and intraperitoneal administration. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tindamax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Timidazole Tinidazol Tinidazole Tinidazolum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tinidazole is a nitroimidazole used to treat trichomoniasis, giardiasis, amebiasis, and bacterial vaginosis. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Tiopronin interact?

•Drug A: Bupropion •Drug B: Tiopronin •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Tiopronin which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tiopronin is indicated for the prevention of kidney stone formation in patients with severe homozygous cystinuria consisting of a urinary cystine concentration greater than 500 mg/day, and who have failed treatment with non-pharmacological measures of increased fluid intake, decreased sodium and protein intake, and urine alkalinization. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Kidney stones form when the solubility limit is exceeded and urine becomes supersaturated with endogenous cystine. Tiopronin is an active reducing agent which undergoes a thiol-disulfide exchange with cystine to form a water-soluble mixed disulfide complex. Thus, the amount of sparingly soluble cystine is reduced. By reducing urinary cystine concentrations below the solubility limit, tiopronin helps reduce cystine stone formation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Tiopronin undergoes slow absorption, reaching peak plasma concentration 3-6 hours after ingestion. In a study of healthy subjects, the bioavailability of total and unbound tiopronin was found to be 63% and 40%, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of tiopronin is high at 455 L, indicating that a large portion of the drug is bound to tissues outside plasma. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tiopronin undergoes extensive protein binding in plasma. It is thought that this occurs through the formation of a disulphide bridge to the free thiol group of albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The principle metabolite of tiopronin is 2-mercaptopropionic acid (2-MPA). Between 10-15% of the drug is metabolized to 2-MPA via hydrolysis. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tiopronin is 100% excreted in urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Tiopronin has a long terminal half life of 53 hours in healthy subjects. However, the unbound drug fraction of tiopronin is eliminated much more rapidly from plasma with a calculated half life of 1.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total renal clearance for the total and unbound fractions of tiopronin were found to be 3.3 and 13.3 L/h respectively. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Long-term carcinogenicity and mutagenicity studies have not been performed with tiopronin. In experimental animal studies, high doses of tiopronin were shown to interfere with the maintenance of pregnancy and viability of a fetus. No neural tube defects were detected when tiopronin was given to mice and rats in doses up to 10 times the highest recommended human dose. However, the manufacturer does not rule out the possibility of teratogenicity, as it has been seen with the drug d-penicillamine, which acts with a similar mechanism to tiopronin. Tiopronin is not recommended for use in breastfeeding mothers and has no established safety in children 9 years old or younger. There have been case reports of tiopronin-related nephropathy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Thiola •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tiopronin is a thiol agent indicated for the prevention of kidney stone formation in patients with severe homozygous cystinuria.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Tiopronin interact? Information: •Drug A: Bupropion •Drug B: Tiopronin •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Tiopronin which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tiopronin is indicated for the prevention of kidney stone formation in patients with severe homozygous cystinuria consisting of a urinary cystine concentration greater than 500 mg/day, and who have failed treatment with non-pharmacological measures of increased fluid intake, decreased sodium and protein intake, and urine alkalinization. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Kidney stones form when the solubility limit is exceeded and urine becomes supersaturated with endogenous cystine. Tiopronin is an active reducing agent which undergoes a thiol-disulfide exchange with cystine to form a water-soluble mixed disulfide complex. Thus, the amount of sparingly soluble cystine is reduced. By reducing urinary cystine concentrations below the solubility limit, tiopronin helps reduce cystine stone formation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Tiopronin undergoes slow absorption, reaching peak plasma concentration 3-6 hours after ingestion. In a study of healthy subjects, the bioavailability of total and unbound tiopronin was found to be 63% and 40%, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of tiopronin is high at 455 L, indicating that a large portion of the drug is bound to tissues outside plasma. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tiopronin undergoes extensive protein binding in plasma. It is thought that this occurs through the formation of a disulphide bridge to the free thiol group of albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The principle metabolite of tiopronin is 2-mercaptopropionic acid (2-MPA). Between 10-15% of the drug is metabolized to 2-MPA via hydrolysis. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tiopronin is 100% excreted in urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Tiopronin has a long terminal half life of 53 hours in healthy subjects. However, the unbound drug fraction of tiopronin is eliminated much more rapidly from plasma with a calculated half life of 1.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total renal clearance for the total and unbound fractions of tiopronin were found to be 3.3 and 13.3 L/h respectively. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Long-term carcinogenicity and mutagenicity studies have not been performed with tiopronin. In experimental animal studies, high doses of tiopronin were shown to interfere with the maintenance of pregnancy and viability of a fetus. No neural tube defects were detected when tiopronin was given to mice and rats in doses up to 10 times the highest recommended human dose. However, the manufacturer does not rule out the possibility of teratogenicity, as it has been seen with the drug d-penicillamine, which acts with a similar mechanism to tiopronin. Tiopronin is not recommended for use in breastfeeding mothers and has no established safety in children 9 years old or younger. There have been case reports of tiopronin-related nephropathy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Thiola •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tiopronin is a thiol agent indicated for the prevention of kidney stone formation in patients with severe homozygous cystinuria. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Tiotropium interact?

•Drug A: Bupropion •Drug B: Tiotropium •Severity: MAJOR •Description: The metabolism of Tiotropium can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tiotropium powder for inhalation is indicated for the maintenance of bronchospasm in COPD and to prevent exacerbations of COPD. A combination tiotropium and olodaterol metered inhalation spray is indicated for maintenance of COPD. A tiotropium inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 12 or more years old. A tiotropium metered inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 6 or more years old. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tiotropium is a long acting antimuscarinic that causes bronchodilation. The effects of tiotropium last over 24 hours and there is a wide therapeutic index as overdoses are uncommon even at doses well above the recommended maximum. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tiotropium is an antagonist of muscarinic receptors M 1 to M 5. Inhibition of the M 3 receptor in the smooth muscle of the lungs leads to relaxation of smooth muscle and bronchodilation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): 33% of an inhaled solution reaches systemic circulation, while oral solutions have a bioavailability of 2-3%. A dry powder for inhalation is 19.5% bioavailable. Tiotropium metered spray for inhalation reaches a maximum concentration in 5-7 minutes. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of tiotropium is 32L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tiotropium is 72% protein bound in plasma. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tiotropium is not heavily metabolized in the body. 74% of an intravenous dose is excreted in the urine as unchanged drug. Tiotropium is nonenzymatically cleaved to the inactive metabolites N-methylscopine and dithienylglycolic acid. In vitro experiments show cytochrome P-450 dependent oxidation and glutathione conjugation to further metabolites. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): 74% of intravenous tiotropium was excreted unchanged in urine. 14% of a dry powder inhalation dose was excreted unchanged in the urine. 24 hour urinary excretion after 21 days of 5µg once daily inhalation in patients with COPD is 18.6% and in patients with asthma is 12.8%. •Half-life (Drug A): 24 hours •Half-life (Drug B): The terminal half life of tiotropium is 24 hours in patients with COPD and 44 hours in patients with asthma. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total clearance of tiotropium is 880mL/min in healthy subjects receiving 5µg daily. The renal clearance of tiotropium was 669mL/min. Patients <65 years old demonstrated a clearance of 365mL/min while patients ≥65 demonstrated a clearance of 271mL/min. This decreased clearance is not associated with increased AUC or C max. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include altered mental status, tremors, abdominal pain, and severe constipation. However, doses of up to 282µg did not lead to systemic anticholinergic effects in a trial of 6 patients. In case of overdose, stop tiotropium and being symptomatic and supportive therapy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Inspiolto Respimat, Spiriva, Spiriva Respimat, Stiolto •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tiotropium is a long-acting bronchodilator used in the management of chronic obstructive pulmonary disease (COPD).

The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Tiotropium interact? Information: •Drug A: Bupropion •Drug B: Tiotropium •Severity: MAJOR •Description: The metabolism of Tiotropium can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tiotropium powder for inhalation is indicated for the maintenance of bronchospasm in COPD and to prevent exacerbations of COPD. A combination tiotropium and olodaterol metered inhalation spray is indicated for maintenance of COPD. A tiotropium inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 12 or more years old. A tiotropium metered inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 6 or more years old. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tiotropium is a long acting antimuscarinic that causes bronchodilation. The effects of tiotropium last over 24 hours and there is a wide therapeutic index as overdoses are uncommon even at doses well above the recommended maximum. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tiotropium is an antagonist of muscarinic receptors M 1 to M 5. Inhibition of the M 3 receptor in the smooth muscle of the lungs leads to relaxation of smooth muscle and bronchodilation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): 33% of an inhaled solution reaches systemic circulation, while oral solutions have a bioavailability of 2-3%. A dry powder for inhalation is 19.5% bioavailable. Tiotropium metered spray for inhalation reaches a maximum concentration in 5-7 minutes. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of tiotropium is 32L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tiotropium is 72% protein bound in plasma. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tiotropium is not heavily metabolized in the body. 74% of an intravenous dose is excreted in the urine as unchanged drug. Tiotropium is nonenzymatically cleaved to the inactive metabolites N-methylscopine and dithienylglycolic acid. In vitro experiments show cytochrome P-450 dependent oxidation and glutathione conjugation to further metabolites. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): 74% of intravenous tiotropium was excreted unchanged in urine. 14% of a dry powder inhalation dose was excreted unchanged in the urine. 24 hour urinary excretion after 21 days of 5µg once daily inhalation in patients with COPD is 18.6% and in patients with asthma is 12.8%. •Half-life (Drug A): 24 hours •Half-life (Drug B): The terminal half life of tiotropium is 24 hours in patients with COPD and 44 hours in patients with asthma. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total clearance of tiotropium is 880mL/min in healthy subjects receiving 5µg daily. The renal clearance of tiotropium was 669mL/min. Patients <65 years old demonstrated a clearance of 365mL/min while patients ≥65 demonstrated a clearance of 271mL/min. This decreased clearance is not associated with increased AUC or C max. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include altered mental status, tremors, abdominal pain, and severe constipation. However, doses of up to 282µg did not lead to systemic anticholinergic effects in a trial of 6 patients. In case of overdose, stop tiotropium and being symptomatic and supportive therapy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Inspiolto Respimat, Spiriva, Spiriva Respimat, Stiolto •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tiotropium is a long-acting bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). Output: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Tipranavir interact?

•Drug A: Bupropion •Drug B: Tipranavir •Severity: MAJOR •Description: The metabolism of Tipranavir can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tipranavir is a non-peptidic protease inhibitor (PI) of HIV. Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Nelfinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tipranavir (TPV) is a non-peptidic HIV-1 protease inhibitor that inhibits the processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Two mechanisms are suggested in regards to the potency of tipranavir: 1. Tipravanir may bind to the active site of the protease enzyme with fewer hydrogen bonds than peptidic protease inhibitors, which results in increased flexibility, allowing it to fit into the active site of the enzyme in viruses that have become resistance to other protease inhibitors. This also enables tipranavir to adjust to amino acid substitutions at the active site. 2. Tipranavir's strong hydrogen bonding interaction with the amide backbone of the protease active site Asp30 may lead to its activity against resistant viruses. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Absorption is limited, although no absolute quantification of absorption is available. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Extensive (> 99.9%), to both human serum albumin and α-1-acid glycoprotein. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 5-6 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral LD 50 in rat is over 5,000 mg/kg. Side effects include thirst and hunger, unexplained weight loss, increased urination, fatigue, and dry, itchy skin. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Aptivus •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tipranavir is a protease inhibitor used to treat HIV-1 resistant to more than 1 protease inhibitor.

The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Tipranavir interact? Information: •Drug A: Bupropion •Drug B: Tipranavir •Severity: MAJOR •Description: The metabolism of Tipranavir can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tipranavir is a non-peptidic protease inhibitor (PI) of HIV. Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Nelfinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tipranavir (TPV) is a non-peptidic HIV-1 protease inhibitor that inhibits the processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Two mechanisms are suggested in regards to the potency of tipranavir: 1. Tipravanir may bind to the active site of the protease enzyme with fewer hydrogen bonds than peptidic protease inhibitors, which results in increased flexibility, allowing it to fit into the active site of the enzyme in viruses that have become resistance to other protease inhibitors. This also enables tipranavir to adjust to amino acid substitutions at the active site. 2. Tipranavir's strong hydrogen bonding interaction with the amide backbone of the protease active site Asp30 may lead to its activity against resistant viruses. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Absorption is limited, although no absolute quantification of absorption is available. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Extensive (> 99.9%), to both human serum albumin and α-1-acid glycoprotein. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 5-6 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral LD 50 in rat is over 5,000 mg/kg. Side effects include thirst and hunger, unexplained weight loss, increased urination, fatigue, and dry, itchy skin. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Aptivus •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tipranavir is a protease inhibitor used to treat HIV-1 resistant to more than 1 protease inhibitor. Output: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Tirofiban interact?

•Drug A: Bupropion •Drug B: Tirofiban •Severity: MINOR •Description: Tirofiban may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For treatment, in combination with heparin, of acute coronary syndrome, including patients who are to be managed medically and those undergoing PTCA or atherectomy. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tirofiban prevents the blood from clotting during episodes of chest pain or a heart attack, or while the patient is undergoing a procedure to treat a blocked coronary artery. It is a non-peptide antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, and inhibits platelet aggregation. When administered intravenously, tirofiban inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. When given according to the recommended regimen, >90% inhibition is attained by the end of the 30-minute infusion. Tirofiban has been recently shown in patients with unstable angina to reduce ischemic events at 48 hours following infusion when compared to standard heparin therapy. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tirofiban is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. Platelet aggregation inhibition is reversible following cessation of the infusion of tirofiban. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 22 to 42 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 65% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Metabolism appears to be limited. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. •Half-life (Drug A): 24 hours •Half-life (Drug B): 2 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 213 - 314 mL/min [Healthy subjects] 152 - 267 mL/min [patients with coronary artery disease] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Aggrastat •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tirofiban Tirofibán Tirofibanum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tirofiban is a platelet aggregation inhibitor used to prevent thrombotic events in non-ST elevated acute coronary syndrome.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Tirofiban interact? Information: •Drug A: Bupropion •Drug B: Tirofiban •Severity: MINOR •Description: Tirofiban may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For treatment, in combination with heparin, of acute coronary syndrome, including patients who are to be managed medically and those undergoing PTCA or atherectomy. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tirofiban prevents the blood from clotting during episodes of chest pain or a heart attack, or while the patient is undergoing a procedure to treat a blocked coronary artery. It is a non-peptide antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, and inhibits platelet aggregation. When administered intravenously, tirofiban inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. When given according to the recommended regimen, >90% inhibition is attained by the end of the 30-minute infusion. Tirofiban has been recently shown in patients with unstable angina to reduce ischemic events at 48 hours following infusion when compared to standard heparin therapy. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tirofiban is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. Platelet aggregation inhibition is reversible following cessation of the infusion of tirofiban. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 22 to 42 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 65% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Metabolism appears to be limited. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. •Half-life (Drug A): 24 hours •Half-life (Drug B): 2 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 213 - 314 mL/min [Healthy subjects] 152 - 267 mL/min [patients with coronary artery disease] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Aggrastat •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tirofiban Tirofibán Tirofibanum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tirofiban is a platelet aggregation inhibitor used to prevent thrombotic events in non-ST elevated acute coronary syndrome. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Tixocortol interact?

•Drug A: Bupropion •Drug B: Tixocortol •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Tixocortol which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tixocortol is indicated for the treatment of rhinitis as a nasal suspension or aerosol. It is also used in the form of lozenges for the treatment of pharyngitis and in the form of enemas or rectal solution for the treatment of ulcerative colitis. Tixocortol can be used orally in a suspension or powder for the treatment of inflammatory conditions. It is also the substance used for the screening of contact allergies to class A steroids. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tixocortol presents the characteristic of local action which reduces significantly the side effects of systemic glucocorticoids. Reports have demonstrated that gastrointestinal administration of tixocortol generates a decrease in abdominal pain, bleeding, and frequency of stools which resulted in an amelioration in the malabsorption laboratory tests. All the effects were independent of suppression of the pituitary-adrenal axis, which was shown by the absence of significant depression of cortisol. Administration of tixocortol as a nasal spray has been shown to respect nasal drainage by the ciliary beats of the pituitary mucosa. The actions of tixocortol have no effect on leukocyte count, blood glucose level, sodium urinary excretion, and immunosupressive activity on lymphocytes. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of tixocortol is similar to other corticosteroids regarding the binding sites and prostaglandin synthesis but the local properties of tixocortol are given by the immediate liver metabolism and transformation withing red blood cells. All the immediate transformations of tixocortol classified it as part of the nonsystemic steroids. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The absorption of tixocortol is the same as in other steroids including hydrocortisone. Oral administration of tixocortol presents a 10-20% bioavailability with a significantly lower plasma Cmax than cortisol. The fast metabolism, larger volume of distribution and low bioavailability donates tixocortol with the absence of systemic activity. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger volume of distribution compared to cortisol of 21.7 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The presence of the C-17 in the corticosteroids is a protein binding site. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tixocortol is rapidly modified within red blood cells and it is immediately metabolized by a first-pass liver metabolism. The metabolites of tixocortol are mainly represented by the formation of sulfo- and glucurono-conjugates which are later hydrolyzed from the conjugate forming neutral steroids. The metabolic transformations are the reduction of the 3-keto and delta 4 system, reduction of the C-20 carbonyl group, oxidation of the C-11 alcohol and cleavage of the side chain at C-17. The specific metabolic pathways of the C-21 thiol ester function were its transformation into methylthio, methylsulfonyl and methylsulfonyl derivatives and reductive cleavage of the C-21-S bond leading to 21-methyl structures. None of the metabolites have affinity for glucocorticoid receptors. This and the extensive metabolism explains the exclusive local activities of tixocortol. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tixocortol has a rapid elimination after continuous metabolism. Urine analysis of oral administration of tixocortol demonstrate a complete lack of unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): Tixocortol presents a shorter half-life than cortisol. •Clearance (Drug A): No clearance available •Clearance (Drug B): Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger clearance rate compared to cortisol of 33.3 L h/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Diverse studies performed on tixocortol proved that this drug is non-toxic and non-immunosupressive. This low toxicity and abscence of immuno supression gave tixocortol the potential to be a lead for topical or local anti-inflammatory treatments. Nevertheless, toxicortol is a potent cutaneous sensitizer, causing a local allergy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tixocortol is a corticosteroid used for the symptomatic treatment of rhinitis, pharyngitis, and ulcerative colitis.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Tixocortol interact? Information: •Drug A: Bupropion •Drug B: Tixocortol •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Tixocortol which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tixocortol is indicated for the treatment of rhinitis as a nasal suspension or aerosol. It is also used in the form of lozenges for the treatment of pharyngitis and in the form of enemas or rectal solution for the treatment of ulcerative colitis. Tixocortol can be used orally in a suspension or powder for the treatment of inflammatory conditions. It is also the substance used for the screening of contact allergies to class A steroids. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tixocortol presents the characteristic of local action which reduces significantly the side effects of systemic glucocorticoids. Reports have demonstrated that gastrointestinal administration of tixocortol generates a decrease in abdominal pain, bleeding, and frequency of stools which resulted in an amelioration in the malabsorption laboratory tests. All the effects were independent of suppression of the pituitary-adrenal axis, which was shown by the absence of significant depression of cortisol. Administration of tixocortol as a nasal spray has been shown to respect nasal drainage by the ciliary beats of the pituitary mucosa. The actions of tixocortol have no effect on leukocyte count, blood glucose level, sodium urinary excretion, and immunosupressive activity on lymphocytes. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of tixocortol is similar to other corticosteroids regarding the binding sites and prostaglandin synthesis but the local properties of tixocortol are given by the immediate liver metabolism and transformation withing red blood cells. All the immediate transformations of tixocortol classified it as part of the nonsystemic steroids. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The absorption of tixocortol is the same as in other steroids including hydrocortisone. Oral administration of tixocortol presents a 10-20% bioavailability with a significantly lower plasma Cmax than cortisol. The fast metabolism, larger volume of distribution and low bioavailability donates tixocortol with the absence of systemic activity. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger volume of distribution compared to cortisol of 21.7 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The presence of the C-17 in the corticosteroids is a protein binding site. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tixocortol is rapidly modified within red blood cells and it is immediately metabolized by a first-pass liver metabolism. The metabolites of tixocortol are mainly represented by the formation of sulfo- and glucurono-conjugates which are later hydrolyzed from the conjugate forming neutral steroids. The metabolic transformations are the reduction of the 3-keto and delta 4 system, reduction of the C-20 carbonyl group, oxidation of the C-11 alcohol and cleavage of the side chain at C-17. The specific metabolic pathways of the C-21 thiol ester function were its transformation into methylthio, methylsulfonyl and methylsulfonyl derivatives and reductive cleavage of the C-21-S bond leading to 21-methyl structures. None of the metabolites have affinity for glucocorticoid receptors. This and the extensive metabolism explains the exclusive local activities of tixocortol. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tixocortol has a rapid elimination after continuous metabolism. Urine analysis of oral administration of tixocortol demonstrate a complete lack of unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): Tixocortol presents a shorter half-life than cortisol. •Clearance (Drug A): No clearance available •Clearance (Drug B): Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger clearance rate compared to cortisol of 33.3 L h/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Diverse studies performed on tixocortol proved that this drug is non-toxic and non-immunosupressive. This low toxicity and abscence of immuno supression gave tixocortol the potential to be a lead for topical or local anti-inflammatory treatments. Nevertheless, toxicortol is a potent cutaneous sensitizer, causing a local allergy. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tixocortol is a corticosteroid used for the symptomatic treatment of rhinitis, pharyngitis, and ulcerative colitis. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Tizanidine interact?

•Drug A: Bupropion •Drug B: Tizanidine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Tizanidine is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tizanidine is indicated for the relief of muscle spasticity, which can interfere with daily activities. The general recommendation is to reserve tizanidine use for periods of time when there is a particular need for relief, as it has a short duration of action. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): A note on spasticity Spasticity is an increase in muscle accompanied by uncontrolled, repetitive contractions of skeletal muscles which are involuntary. The patient suffering from muscle spasticity may have reduced mobility and high levels of pain, contributing to poor quality of life and problems performing activities of personal hygiene and care. General effects Tizanidine is a rapidly acting drug used for the relief of muscle spasticity when it is required for performing specific activities. It acts as an agonist at Alpha-2 adrenergic receptor sites and relieves symptoms of muscle spasticity, allowing the continuation of normal daily activities. In animal models, tizanidine has not been shown to exert direct effects on skeletal muscle fibers or the neuromuscular junction, and has shown no significant effect on monosynaptic spinal reflexes (consisting of the communication between only 1 sensory neuron and 1 motor neuron). The frequency of muscle spasm and clonus are shown to be decreased by tizanidine. Tizanidine shows a stronger action on polysynaptic reflexes, which involve several interneurons (relay neurons) communicating with motor neurons stimulating muscle movement. Effects on blood pressure and heart rate This drug decreases heart rate and blood pressure in humans. Despite this, rebound hypertension and tachycardia along with increased spasticity can occur when tizanidine is abruptly discontinued. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons via agonist actions at Alpha-2 adrenergic receptor sites. This drug is centrally acting and leads to a reduction in the release of excitatory amino acids like glutamate and aspartate, which cause neuronal firing that leads to muscle spasm. The above reduction and excitatory neurotransmitter release results in presynaptic inhibition of motor neurons. The strongest effect of tizanidine has been shown to occur on spinal polysynaptic pathways. The anti-nociceptive and anticonvulsant activities of tizanidine may also be attributed to agonist action on Alpha-2 receptors. Tizanidine also binds with weaker affinity to the Alpha-1 receptors, explaining its slight and temporary effect on the cardiovascular system. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): This drug undergoes significant first-pass metabolism. After the administration of an oral dose, tizanidine is mostly absorbed. The absolute oral bioavailability of tizanidine is measured to be about 40%. Effect of food on absorption Food has been shown to increase absorption for both the tablets and capsules. The increase in absorption with the tablet (about 30%) was noticeably higher than the capsule (~10%). When the capsule and tablet were administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. It is therefore advisable to take this drug with food for increased absorption, especially in tablet form. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Extensively distributed throughout the body. The average steady-state volume of distribution is 2.4 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): About 30% bound to plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): About 95% of the ingested dose of tizanidine is metabolized. The main enzyme involved in the hepatic metabolism of tizanidine is CYP1A2. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): This drug is mainly eliminated by the kidney. •Half-life (Drug A): 24 hours •Half-life (Drug B): Approximately 2.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): A note on renal impairment Tizanidine clearance is found to be decreased by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. This drug should be used with caution in patients with renal impairment. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD50 information Oral LD50 (rat): 414 mg/kg; Subcutaneous LD50 (rat): 282 mg/kg; Oral LD50 (mouse): 235 mg/kg Use in pregnancy Animal studies have determined that this drug causes fetal harm. Studies have not been performed in humans, and it is advisable to ensure that tizanidine use in pregnant women should be reserved for cases in which possible benefit clearly outweighs the possible risk to mother and unborn child. Use in breastfeeding In studies of rat models, this tizanidine was found excreted in the breastmilk with a milk-to-blood ratio of 1.8:1. In young nursing rats, abnormal results were obtained in tests indicative of central nervous system function. Various developmental changes that may have been attributable to the drug were observed. It is unknown whether tizanidine is excreted in human milk. It is a lipid-soluble drug, however, and likely to be excreted into breast milk. Carcinogenesis and mutagenesis No signs of carcinogenicity were observed in two dietary studies performed in rodent models. Tizanidine was given to mice for 78 weeks at doses reaching a maximum 16 mg/kg (equivalent to twice the maximum recommended human dose). In addition, the drug was given to rats for 104 weeks at doses reaching 9 mg/kg (equivalent to 2.5 times the maximum recommended human dose). There was a lack of a statistically significant increase in the occurrence of tumors in either study group. Tizanidine was not found to be mutagenic or clastogenic in several laboratory essays, including the bacterial Ames test, the mammalian gene mutation test, in addition to the chromosomal aberration test in Chinese hamster cells and several other assays. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zanaflex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tizanidin Tizanidina Tizanidine Tizanidinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tizanidine is an alpha-2 adrenergic agonist used for the short-term treatment of muscle spasticity.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Tizanidine interact? Information: •Drug A: Bupropion •Drug B: Tizanidine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Tizanidine is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tizanidine is indicated for the relief of muscle spasticity, which can interfere with daily activities. The general recommendation is to reserve tizanidine use for periods of time when there is a particular need for relief, as it has a short duration of action. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): A note on spasticity Spasticity is an increase in muscle accompanied by uncontrolled, repetitive contractions of skeletal muscles which are involuntary. The patient suffering from muscle spasticity may have reduced mobility and high levels of pain, contributing to poor quality of life and problems performing activities of personal hygiene and care. General effects Tizanidine is a rapidly acting drug used for the relief of muscle spasticity when it is required for performing specific activities. It acts as an agonist at Alpha-2 adrenergic receptor sites and relieves symptoms of muscle spasticity, allowing the continuation of normal daily activities. In animal models, tizanidine has not been shown to exert direct effects on skeletal muscle fibers or the neuromuscular junction, and has shown no significant effect on monosynaptic spinal reflexes (consisting of the communication between only 1 sensory neuron and 1 motor neuron). The frequency of muscle spasm and clonus are shown to be decreased by tizanidine. Tizanidine shows a stronger action on polysynaptic reflexes, which involve several interneurons (relay neurons) communicating with motor neurons stimulating muscle movement. Effects on blood pressure and heart rate This drug decreases heart rate and blood pressure in humans. Despite this, rebound hypertension and tachycardia along with increased spasticity can occur when tizanidine is abruptly discontinued. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons via agonist actions at Alpha-2 adrenergic receptor sites. This drug is centrally acting and leads to a reduction in the release of excitatory amino acids like glutamate and aspartate, which cause neuronal firing that leads to muscle spasm. The above reduction and excitatory neurotransmitter release results in presynaptic inhibition of motor neurons. The strongest effect of tizanidine has been shown to occur on spinal polysynaptic pathways. The anti-nociceptive and anticonvulsant activities of tizanidine may also be attributed to agonist action on Alpha-2 receptors. Tizanidine also binds with weaker affinity to the Alpha-1 receptors, explaining its slight and temporary effect on the cardiovascular system. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): This drug undergoes significant first-pass metabolism. After the administration of an oral dose, tizanidine is mostly absorbed. The absolute oral bioavailability of tizanidine is measured to be about 40%. Effect of food on absorption Food has been shown to increase absorption for both the tablets and capsules. The increase in absorption with the tablet (about 30%) was noticeably higher than the capsule (~10%). When the capsule and tablet were administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. It is therefore advisable to take this drug with food for increased absorption, especially in tablet form. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Extensively distributed throughout the body. The average steady-state volume of distribution is 2.4 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): About 30% bound to plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): About 95% of the ingested dose of tizanidine is metabolized. The main enzyme involved in the hepatic metabolism of tizanidine is CYP1A2. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): This drug is mainly eliminated by the kidney. •Half-life (Drug A): 24 hours •Half-life (Drug B): Approximately 2.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): A note on renal impairment Tizanidine clearance is found to be decreased by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. This drug should be used with caution in patients with renal impairment. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD50 information Oral LD50 (rat): 414 mg/kg; Subcutaneous LD50 (rat): 282 mg/kg; Oral LD50 (mouse): 235 mg/kg Use in pregnancy Animal studies have determined that this drug causes fetal harm. Studies have not been performed in humans, and it is advisable to ensure that tizanidine use in pregnant women should be reserved for cases in which possible benefit clearly outweighs the possible risk to mother and unborn child. Use in breastfeeding In studies of rat models, this tizanidine was found excreted in the breastmilk with a milk-to-blood ratio of 1.8:1. In young nursing rats, abnormal results were obtained in tests indicative of central nervous system function. Various developmental changes that may have been attributable to the drug were observed. It is unknown whether tizanidine is excreted in human milk. It is a lipid-soluble drug, however, and likely to be excreted into breast milk. Carcinogenesis and mutagenesis No signs of carcinogenicity were observed in two dietary studies performed in rodent models. Tizanidine was given to mice for 78 weeks at doses reaching a maximum 16 mg/kg (equivalent to twice the maximum recommended human dose). In addition, the drug was given to rats for 104 weeks at doses reaching 9 mg/kg (equivalent to 2.5 times the maximum recommended human dose). There was a lack of a statistically significant increase in the occurrence of tumors in either study group. Tizanidine was not found to be mutagenic or clastogenic in several laboratory essays, including the bacterial Ames test, the mammalian gene mutation test, in addition to the chromosomal aberration test in Chinese hamster cells and several other assays. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zanaflex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tizanidin Tizanidina Tizanidine Tizanidinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tizanidine is an alpha-2 adrenergic agonist used for the short-term treatment of muscle spasticity. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Tobramycin interact?

•Drug A: Bupropion •Drug B: Tobramycin •Severity: MODERATE •Description: Bupropion may decrease the excretion rate of Tobramycin which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Inhaled tobramycin is indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa, but is not recommended in patients under six years of age, those with forced expiratory volume in 1 second (FEV 1 ) <25 or >80% predicted, or in those with Burkholderia cepacia. Tobramycin applied topically to the eyes is indicated for the treatment of external eye (and adjoining structure) infections by susceptible bacteria. Tobramycin injection is indicated in adult and pediatric patients for the treatment of serious bacterial infections, including septicemia (caused by P. aeruginosa, Escherichia coli, and Klebsiella spp.), lower respiratory tract infections (caused by P. aeruginosa, Klebsiella spp., Enterobacter spp., Serratia spp., E. coli, and Staphylococcus aureus, both penicillinase and non-penicillinase-producing strains), serious central-nervous-system infections (meningitis, caused by susceptible organisms), intra-abdominal infections including peritonitis (caused by E. coli, Klebsiella spp., and Enterobacter spp.), skin, bone, and skin structure infections (caused by P. aeruginosa, Proteus spp., E. coli, Klebsiella spp., Enterobacter spp., Serratia spp. and S. aureus ), and complicated and recurrent urinary tract infections (caused by P. aeruginosa, Proteus spp., E. coli, Klebsiella spp., Enterobacter spp., Serratia spp., S. aureus, Providencia spp., and Citrobacter spp.). Aminoglycosides, including tobramycin, should generally not be used in uncomplicated urinary tract infections or staphylococcal infections unless less toxic antibiotics cannot be used and the bacteria in question are known to be sensitive to aminoglycosides. As with all antibiotics, tobramycin use should be limited to cases where bacterial infections are known or strongly suspected to be caused by sensitive organisms, and the possible emergence of resistance should be monitored closely. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tobramycin is an aminoglycoside antibiotic derived from the actinomycete Streptomyces tenebrarius. It has a broad spectrum of activity against Gram-negative bacteria, including Enterobacteriaceae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Moraxella lacunata, Proteus spp., Haemophilus spp., Acinetobacter spp., Neisseria spp., and, importantly, Pseudomonas aeruginosa. Aminoglycosides also generally retain activity against the biothreat agents Yersinia pestis and Francisella tularensis. In addition, aminoglycosides are active against some Gram-positive bacteria such as Staphylococcus spp., including methicillin-resistant (MRSA) and vancomycin-resistant strains, Streptococcus spp., and Mycobacterium spp. Like other aminoglycosides, tobramycin is taken up and retained by proximal tubule and cochlear cells in the kidney and ear, respectively, and hence carries a risk of nephrotoxicity and ototoxicity. There is also a risk of neuromuscular block, which may be more pronounced in patients with preexisting neuromuscular disorders such as myasthenia gravis or Parkinson's disease. Aminoglycosides can cross the placenta, resulting in total, irreversible, bilateral congenital deafness in babies born to mothers who were administered an aminoglycoside during pregnancy. Due to the low systemic absorption of inhaled and topical tobramycin formulations, these effects are more pronounced with injected tobramycin than with other formulations. However, all formulations carry a risk of hypersensitivity reactions, including potentially fatal cutaneous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tobramycin is a 4,6-disubstituted 2-deoxystreptamine (DOS) ring-containing aminoglycoside antibiotic with activity against various Gram-negative and some Gram-positive bacteria. The mechanism of action of tobramycin has not been unambiguously elucidated, and some insights into its mechanism rely on results using similar aminoglycosides. In general, like other aminoglycosides, tobramycin is bactericidal and exhibits both immediate and delayed killing, which are attributed to different mechanisms, as outlined below. Aminoglycosides are polycationic at physiological pH, such that they readily bind to bacterial membranes ("ionic binding"); this includes binding to lipopolysaccharide and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acid and phospholipids within the cell membrane of Gram-positive bacteria. This binding displaces divalent cations and increases membrane permeability, which allows aminoglycoside entry. Additional aminoglycoside entry ("energy-dependent phase I") into the cytoplasm requires the proton-motive force, allowing access of the aminoglycoside to its primary intracellular target of the bacterial 30S ribosome. Mistranslated proteins produced as a result of aminoglycoside binding to the ribosome (see below) integrate into and disrupt the cell membrane, which allows more of the aminoglycoside into the cell ("energy-dependent phase II"). Hence, tobramycin and other aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modelling support this two-mechanism model. Inhibition of protein synthesis was the first recognized effect of aminoglycoside antibiotics. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site. Overall, aminoglycoside binding has several negative effects, including inhibiting translation initiation and elongation and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit. Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation; mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above. Although direct mutation of the 16S rRNA is a rare resistance mechanism, due to the gene being present in numerous copies, posttranscriptional 16S rRNA modification by 16S rRNA methyltransferases (16S-RMTases) at the N7 position of G1405 or the N1 position of A1408 are common resistance mechanisms in aminoglycoside-resistant bacteria. These mutants also further support the proposed mechanism of action of aminoglycosides. Direct modification of the aminoglycoside itself through acetylation, adenylation, and phosphorylation by aminoglycoside-modifying enzymes (AMEs) are also commonly encountered resistance mutations. Finally, due to the requirement for active transport of aminoglycosides across bacterial membranes, they are not active against obligately anaerobic bacteria. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Tobramycin administered by inhalation in cystic fibrosis patients showed greater variability in sputum as compared to serum. After a single 112 mg dose, the serum C max was 1.02 ± 0.53 μg/mL, which was reached in one hour (T max ), while the sputum C max was 1048 ± 1080 μg/g. Comparatively, for a 300 mg dose, the serum C max was 1.04 ± 0.58 μg/mL, which was also reached within one hour, while the sputum C max was 737 ± 1028 μg/g. The systemic exposure (AUC 0-12 ) was also similar between the two doses, at 4.6 ± 2.0 μg∙h/mL for the 112 mg dose and 4.8 ± 2.5 μg∙h/mL for the 300 mg dose. When tobramycin was administered over a four-week cycle at 112 mg twice daily, the C max measured one hour after dosing ranged from 1.48 ± 0.69 μg/mL to 1.99 ± 0.59 μg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Inhalation tobramycin had an apparent volume of distribution in the central compartment of 85.1 L for a typical cystic fibrosis patient. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tobramycin binding to serum proteins is negligible. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tobramycin is not appreciably metabolized. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tobramycin is primarily excreted unchanged in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Tobramycin has an apparent serum terminal half-life of ~3 hours following a single 112 mg inhaled dose in cystic fibrosis patients. •Clearance (Drug A): No clearance available •Clearance (Drug B): Inhaled tobramycin has an apparent serum clearance of 14.5 L/h in cystic fibrosis patients aged 6-58 years. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Toxicity information regarding tobramycin is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nephrotoxicity, ototoxicity, neuromuscular blockade, and respiratory failure/paralysis. Symptomatic and supportive measures are recommended; hemodialysis may help clear excess tobramycin. Accidental ingestion of tobramycin is unlikely to result in an overdose, as aminoglycosides are poorly absorbed in the gastrointestinal tract. Poor gastrointestinal absorption is reflected in animal studies. When administered by the intraperitoneal or subcutaneous route, the LD50 for mice and rats ranges from 367-1030 mg/kg while the oral LD50 values are more than 7500 mg/kg. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Bethkis, Kitabis, Tobi, Tobi Podhaler Weekly Kit, Tobradex, Tobrex, Zylet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3'-Deoxykanamycin B Nebramycin 6 Tobramicina Tobramycin Tobramycine Tobramycinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tobramycin is an aminoglycoside antibiotic used to treat cystic fibrosis-associated bacterial, lower respiratory tract, urinary tract, eye, skin, bone, and skin structure infections.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. The severity of the interaction is moderate.

Question: Does Bupropion and Tobramycin interact? Information: •Drug A: Bupropion •Drug B: Tobramycin •Severity: MODERATE •Description: Bupropion may decrease the excretion rate of Tobramycin which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Inhaled tobramycin is indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa, but is not recommended in patients under six years of age, those with forced expiratory volume in 1 second (FEV 1 ) <25 or >80% predicted, or in those with Burkholderia cepacia. Tobramycin applied topically to the eyes is indicated for the treatment of external eye (and adjoining structure) infections by susceptible bacteria. Tobramycin injection is indicated in adult and pediatric patients for the treatment of serious bacterial infections, including septicemia (caused by P. aeruginosa, Escherichia coli, and Klebsiella spp.), lower respiratory tract infections (caused by P. aeruginosa, Klebsiella spp., Enterobacter spp., Serratia spp., E. coli, and Staphylococcus aureus, both penicillinase and non-penicillinase-producing strains), serious central-nervous-system infections (meningitis, caused by susceptible organisms), intra-abdominal infections including peritonitis (caused by E. coli, Klebsiella spp., and Enterobacter spp.), skin, bone, and skin structure infections (caused by P. aeruginosa, Proteus spp., E. coli, Klebsiella spp., Enterobacter spp., Serratia spp. and S. aureus ), and complicated and recurrent urinary tract infections (caused by P. aeruginosa, Proteus spp., E. coli, Klebsiella spp., Enterobacter spp., Serratia spp., S. aureus, Providencia spp., and Citrobacter spp.). Aminoglycosides, including tobramycin, should generally not be used in uncomplicated urinary tract infections or staphylococcal infections unless less toxic antibiotics cannot be used and the bacteria in question are known to be sensitive to aminoglycosides. As with all antibiotics, tobramycin use should be limited to cases where bacterial infections are known or strongly suspected to be caused by sensitive organisms, and the possible emergence of resistance should be monitored closely. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tobramycin is an aminoglycoside antibiotic derived from the actinomycete Streptomyces tenebrarius. It has a broad spectrum of activity against Gram-negative bacteria, including Enterobacteriaceae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Moraxella lacunata, Proteus spp., Haemophilus spp., Acinetobacter spp., Neisseria spp., and, importantly, Pseudomonas aeruginosa. Aminoglycosides also generally retain activity against the biothreat agents Yersinia pestis and Francisella tularensis. In addition, aminoglycosides are active against some Gram-positive bacteria such as Staphylococcus spp., including methicillin-resistant (MRSA) and vancomycin-resistant strains, Streptococcus spp., and Mycobacterium spp. Like other aminoglycosides, tobramycin is taken up and retained by proximal tubule and cochlear cells in the kidney and ear, respectively, and hence carries a risk of nephrotoxicity and ototoxicity. There is also a risk of neuromuscular block, which may be more pronounced in patients with preexisting neuromuscular disorders such as myasthenia gravis or Parkinson's disease. Aminoglycosides can cross the placenta, resulting in total, irreversible, bilateral congenital deafness in babies born to mothers who were administered an aminoglycoside during pregnancy. Due to the low systemic absorption of inhaled and topical tobramycin formulations, these effects are more pronounced with injected tobramycin than with other formulations. However, all formulations carry a risk of hypersensitivity reactions, including potentially fatal cutaneous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tobramycin is a 4,6-disubstituted 2-deoxystreptamine (DOS) ring-containing aminoglycoside antibiotic with activity against various Gram-negative and some Gram-positive bacteria. The mechanism of action of tobramycin has not been unambiguously elucidated, and some insights into its mechanism rely on results using similar aminoglycosides. In general, like other aminoglycosides, tobramycin is bactericidal and exhibits both immediate and delayed killing, which are attributed to different mechanisms, as outlined below. Aminoglycosides are polycationic at physiological pH, such that they readily bind to bacterial membranes ("ionic binding"); this includes binding to lipopolysaccharide and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acid and phospholipids within the cell membrane of Gram-positive bacteria. This binding displaces divalent cations and increases membrane permeability, which allows aminoglycoside entry. Additional aminoglycoside entry ("energy-dependent phase I") into the cytoplasm requires the proton-motive force, allowing access of the aminoglycoside to its primary intracellular target of the bacterial 30S ribosome. Mistranslated proteins produced as a result of aminoglycoside binding to the ribosome (see below) integrate into and disrupt the cell membrane, which allows more of the aminoglycoside into the cell ("energy-dependent phase II"). Hence, tobramycin and other aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modelling support this two-mechanism model. Inhibition of protein synthesis was the first recognized effect of aminoglycoside antibiotics. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site. Overall, aminoglycoside binding has several negative effects, including inhibiting translation initiation and elongation and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit. Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation; mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above. Although direct mutation of the 16S rRNA is a rare resistance mechanism, due to the gene being present in numerous copies, posttranscriptional 16S rRNA modification by 16S rRNA methyltransferases (16S-RMTases) at the N7 position of G1405 or the N1 position of A1408 are common resistance mechanisms in aminoglycoside-resistant bacteria. These mutants also further support the proposed mechanism of action of aminoglycosides. Direct modification of the aminoglycoside itself through acetylation, adenylation, and phosphorylation by aminoglycoside-modifying enzymes (AMEs) are also commonly encountered resistance mutations. Finally, due to the requirement for active transport of aminoglycosides across bacterial membranes, they are not active against obligately anaerobic bacteria. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Tobramycin administered by inhalation in cystic fibrosis patients showed greater variability in sputum as compared to serum. After a single 112 mg dose, the serum C max was 1.02 ± 0.53 μg/mL, which was reached in one hour (T max ), while the sputum C max was 1048 ± 1080 μg/g. Comparatively, for a 300 mg dose, the serum C max was 1.04 ± 0.58 μg/mL, which was also reached within one hour, while the sputum C max was 737 ± 1028 μg/g. The systemic exposure (AUC 0-12 ) was also similar between the two doses, at 4.6 ± 2.0 μg∙h/mL for the 112 mg dose and 4.8 ± 2.5 μg∙h/mL for the 300 mg dose. When tobramycin was administered over a four-week cycle at 112 mg twice daily, the C max measured one hour after dosing ranged from 1.48 ± 0.69 μg/mL to 1.99 ± 0.59 μg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Inhalation tobramycin had an apparent volume of distribution in the central compartment of 85.1 L for a typical cystic fibrosis patient. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tobramycin binding to serum proteins is negligible. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tobramycin is not appreciably metabolized. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tobramycin is primarily excreted unchanged in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Tobramycin has an apparent serum terminal half-life of ~3 hours following a single 112 mg inhaled dose in cystic fibrosis patients. •Clearance (Drug A): No clearance available •Clearance (Drug B): Inhaled tobramycin has an apparent serum clearance of 14.5 L/h in cystic fibrosis patients aged 6-58 years. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Toxicity information regarding tobramycin is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nephrotoxicity, ototoxicity, neuromuscular blockade, and respiratory failure/paralysis. Symptomatic and supportive measures are recommended; hemodialysis may help clear excess tobramycin. Accidental ingestion of tobramycin is unlikely to result in an overdose, as aminoglycosides are poorly absorbed in the gastrointestinal tract. Poor gastrointestinal absorption is reflected in animal studies. When administered by the intraperitoneal or subcutaneous route, the LD50 for mice and rats ranges from 367-1030 mg/kg while the oral LD50 values are more than 7500 mg/kg. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Bethkis, Kitabis, Tobi, Tobi Podhaler Weekly Kit, Tobradex, Tobrex, Zylet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3'-Deoxykanamycin B Nebramycin 6 Tobramicina Tobramycin Tobramycine Tobramycinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tobramycin is an aminoglycoside antibiotic used to treat cystic fibrosis-associated bacterial, lower respiratory tract, urinary tract, eye, skin, bone, and skin structure infections. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. The severity of the interaction is moderate.

Does Bupropion and Tocilizumab interact?

•Drug A: Bupropion •Drug B: Tocilizumab •Severity: MODERATE •Description: The metabolism of Bupropion can be increased when combined with Tocilizumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. Tocilizumab is also used to treat coronavirus disease 2019 (COVID-19) in adults who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tocilizumab is an IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions. Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index. Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts. IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and α-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin. IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation. Tocilizumab binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): A 162mg subcutaneous dose given weekly has a C max of 51.3±23.2µg/mL and an AUC of 8254±3833µg*h/mL. A 162mg subcutaneous dose given every 2 weeks has a C max of 13±8.3µg/mL and an AUC of 3460±2530µg*h/mL. A 162mg subcutaneous dose given every 4 weeks has a C max of 154±42µg/mL and an AUC of 39216±14304µg*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In rheumatoid arthritis patients, the central volume of distribution is 3.5L, the peripheral volume of distribution is 2.9L, and the volume of distribution at steady state is 6.4L. In giant cell arteritis patients, the central volume of distribution is 4.09L, the peripheral volume of distribution if 3.37L, and the volume of distribution at steady state is 7.46L. In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1.98L, the peripheral volume of distribution is 2.1L, and the volume of distribution at steady state is 4.08L. In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1.87L, the peripheral volume of distribution is 2.14L, and the volume of distribution at steady state is 4.01L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Data regarding the serum protein binding of tocilizumab is not readily available. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tocilizumab, like other monoclonal antibodies, is expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Data regarding the exact route of elimination of monoclonal antibodies is not readily available. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half life of tocilizumab is concentration dependent. The terminal half life in rheumatoid arthritis patients is 21.5 days. The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The linear clearance in rheumatoid arthritis patients is 12.5mL/h, in giant cell arteritis patients is 6.7mL/h, in polyarticular juvenile idiopathic arthritis patients is 5.8mL/h, and in systemic juvenile idiopathic arthritis is 5.7mL/h. Clearance is dose dependent and changes from non linear at low doses to linear at higher doses. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Data regarding overdoses of tocilizumab are not readily available. Patients experiencing an overdose may develop neutropenia. In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Actemra, RoActemra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tocilizumab is an interleukin-6 (IL-6) receptor antagonist used to treat Cytokine Release Syndrome (CRS), Systemic Juvenile Idiopathic Arthritis (sJIA), Giant Cell Arteritis (GCA), and Rheumatoid Arthritis (RA).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Bupropion and Tocilizumab interact? Information: •Drug A: Bupropion •Drug B: Tocilizumab •Severity: MODERATE •Description: The metabolism of Bupropion can be increased when combined with Tocilizumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. Tocilizumab is also used to treat coronavirus disease 2019 (COVID-19) in adults who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tocilizumab is an IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions. Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index. Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts. IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and α-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin. IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation. Tocilizumab binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): A 162mg subcutaneous dose given weekly has a C max of 51.3±23.2µg/mL and an AUC of 8254±3833µg*h/mL. A 162mg subcutaneous dose given every 2 weeks has a C max of 13±8.3µg/mL and an AUC of 3460±2530µg*h/mL. A 162mg subcutaneous dose given every 4 weeks has a C max of 154±42µg/mL and an AUC of 39216±14304µg*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In rheumatoid arthritis patients, the central volume of distribution is 3.5L, the peripheral volume of distribution is 2.9L, and the volume of distribution at steady state is 6.4L. In giant cell arteritis patients, the central volume of distribution is 4.09L, the peripheral volume of distribution if 3.37L, and the volume of distribution at steady state is 7.46L. In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1.98L, the peripheral volume of distribution is 2.1L, and the volume of distribution at steady state is 4.08L. In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1.87L, the peripheral volume of distribution is 2.14L, and the volume of distribution at steady state is 4.01L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Data regarding the serum protein binding of tocilizumab is not readily available. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tocilizumab, like other monoclonal antibodies, is expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Data regarding the exact route of elimination of monoclonal antibodies is not readily available. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half life of tocilizumab is concentration dependent. The terminal half life in rheumatoid arthritis patients is 21.5 days. The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The linear clearance in rheumatoid arthritis patients is 12.5mL/h, in giant cell arteritis patients is 6.7mL/h, in polyarticular juvenile idiopathic arthritis patients is 5.8mL/h, and in systemic juvenile idiopathic arthritis is 5.7mL/h. Clearance is dose dependent and changes from non linear at low doses to linear at higher doses. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Data regarding overdoses of tocilizumab are not readily available. Patients experiencing an overdose may develop neutropenia. In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Actemra, RoActemra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tocilizumab is an interleukin-6 (IL-6) receptor antagonist used to treat Cytokine Release Syndrome (CRS), Systemic Juvenile Idiopathic Arthritis (sJIA), Giant Cell Arteritis (GCA), and Rheumatoid Arthritis (RA). Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Bupropion and Tocopherol interact?

•Drug A: Bupropion •Drug B: Tocopherol •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Tocopherol which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tocopherol can be used as a dietary supplement for patients with a deficit of vitamin E; this is mainly prescribed in the alpha form. Vitamin E deficiency is rare, and it is primarily found in premature babies of very low birth weight, patients with fat malabsorption or patients with abetalipoproteinemia. Tocopherol, due to its antioxidant properties, is studied for its use in prevention or treatment in different complex diseases such as cancer, atherosclerosis, cardiovascular diseases, and age-related macular degeneration. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): The antioxidant effects of tocopherol can be translated into different changes at the pharmacodynamic level. In vitro studies have shown that this antioxidant activity can produce modification in protein kinase C (PKC) which will later be translated into an inhibition of cell death. Some other derivate effects are the anti-inflammatory properties of tocopherol which can be related to the modulation of cytokines or prostaglandins, prostanoids and thromboxanes. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tocopherol acts as a radical scavenger. It mainly acts as an antioxidant for lipid bilayers. Tocopherol's functions depend on the H-atom donating ability, location, and movement within the membrane, as well as the efficiency in the radical recycling by some cytosolic reductants such as ascorbate. Tocopherol actions are related to the trap of radicals, and it has been shown that even in the absence of substituents in the ortho-positions, tocopherol can trap more than two radicals. The type of radicals available for tocopherol are alkyl and peroxy. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The absorption of tocopherol in the digestive tract requires the presence of fat. The bioavailability of tocopherols is highly dependent on the type of isomer that is administered where the alpha-tocopherol can present a bioavailability of 36%. This isomer specificity also determines the intestinal permeability in which the gamma-tocopherol presents a very low permeability. After oral administration, the C max was 1353.79 ng/ml for δ-tocopherol, 547.45 ng/ml for γ-tocopherol, 704.16 ng/ml for β-tocopherol, and 2754.36 ng/ml for α-tocopherol. The T max is three to four hours for δ-tocopherol, γ-tocopherol, and β-tocopherol and about six hours for α-tocopherol. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution was 0.284 ± 0.021 mL for δ-tocopherol, 0.799 ± 0.047 mL for γ-tocopherol, and 0.556 ± 0.046 mL for β-tocopherol. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): There has not been described a specific plasma transport protein for tocopherol but it is thought that it is highly bound to lipoproteins such as VLDL, HDL and chylomicrons. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Excess tocopherol is converted into their corresponding carboxyethylhydroxychroman (CEHC), based on the isomer of tocopherol. More deeply, the metabolism of tocopherol begins with the hepatic metabolism which is led by a CYP4F2/CYP3A4-dependent ω-hydroxylation of the side chains which leads to the formation of 13'-carboxychromanol. The metabolic pathway is followed by five cycles of β-oxidation. The β-oxidation cycles function by shortening the side chains, the first cycle results in the formation of carboxydimethyldecylhydroxychromanol followed by carboxymethyloctylhydroxychromanol. These two metabolites are categorized as long-chain metabolites and they are not excreted in the urine. Some intermediate-chain metabolites that are products of two rounds of β-oxidation are carboxymethylhexylhydroxychromanol and carboxymethylbutylhydroxychromanol. These intermediate-chain metabolites can be found in human feces and urine. The catabolic end-product of tocopherols, as stated before, is CEHC which can be largely found in urine and feces. Two new metabolites have been detected in human and mice feces. These new metabolites are 12'-hydroxychromanol and 11'-hydroxychromanol. Because of their chemistry, it is thought that these metabolites can be the evidence for a ω-1 and ω-2 hydroxylation which leads to an impaired oxidation of 12'-OH followed side-chain truncation. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): The pharmacokinetic profile of tocopherol indicates a longer time of excretion for tocopherols when compared to tocotrienols. The different conjugated metabolites are excreted in the urine or feces depending on the length of their side-chain. Due to their polarity, intermediate-chain metabolites and short-chain metabolites are excreted via urine as glucoside conjugates. A mixture of all the metabolites and precursors can be found in feces. The long-chain metabolites correspond to >60% of the total metabolites in feces. It is estimated that the fecal excretion accounts for even 80% of the administered dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life ranged from 2.44 to 3.02 hours for δ-tocopherol, γ-tocopherol, and β-tocopherol. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance ranged from 0.081 to 0.190 L/h for δ-tocopherol, γ-tocopherol, and β-tocopherol. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Tocopherols are considered as non-toxic but if very high doses are administered, there are reports of hemorrhagic activity. Reproductive and developmental toxicity tests are negative. These negative results were also observed in the analysis of mutagenicity and carcinogenicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): No summary available

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Tocopherol interact? Information: •Drug A: Bupropion •Drug B: Tocopherol •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Tocopherol which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tocopherol can be used as a dietary supplement for patients with a deficit of vitamin E; this is mainly prescribed in the alpha form. Vitamin E deficiency is rare, and it is primarily found in premature babies of very low birth weight, patients with fat malabsorption or patients with abetalipoproteinemia. Tocopherol, due to its antioxidant properties, is studied for its use in prevention or treatment in different complex diseases such as cancer, atherosclerosis, cardiovascular diseases, and age-related macular degeneration. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): The antioxidant effects of tocopherol can be translated into different changes at the pharmacodynamic level. In vitro studies have shown that this antioxidant activity can produce modification in protein kinase C (PKC) which will later be translated into an inhibition of cell death. Some other derivate effects are the anti-inflammatory properties of tocopherol which can be related to the modulation of cytokines or prostaglandins, prostanoids and thromboxanes. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tocopherol acts as a radical scavenger. It mainly acts as an antioxidant for lipid bilayers. Tocopherol's functions depend on the H-atom donating ability, location, and movement within the membrane, as well as the efficiency in the radical recycling by some cytosolic reductants such as ascorbate. Tocopherol actions are related to the trap of radicals, and it has been shown that even in the absence of substituents in the ortho-positions, tocopherol can trap more than two radicals. The type of radicals available for tocopherol are alkyl and peroxy. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The absorption of tocopherol in the digestive tract requires the presence of fat. The bioavailability of tocopherols is highly dependent on the type of isomer that is administered where the alpha-tocopherol can present a bioavailability of 36%. This isomer specificity also determines the intestinal permeability in which the gamma-tocopherol presents a very low permeability. After oral administration, the C max was 1353.79 ng/ml for δ-tocopherol, 547.45 ng/ml for γ-tocopherol, 704.16 ng/ml for β-tocopherol, and 2754.36 ng/ml for α-tocopherol. The T max is three to four hours for δ-tocopherol, γ-tocopherol, and β-tocopherol and about six hours for α-tocopherol. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution was 0.284 ± 0.021 mL for δ-tocopherol, 0.799 ± 0.047 mL for γ-tocopherol, and 0.556 ± 0.046 mL for β-tocopherol. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): There has not been described a specific plasma transport protein for tocopherol but it is thought that it is highly bound to lipoproteins such as VLDL, HDL and chylomicrons. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Excess tocopherol is converted into their corresponding carboxyethylhydroxychroman (CEHC), based on the isomer of tocopherol. More deeply, the metabolism of tocopherol begins with the hepatic metabolism which is led by a CYP4F2/CYP3A4-dependent ω-hydroxylation of the side chains which leads to the formation of 13'-carboxychromanol. The metabolic pathway is followed by five cycles of β-oxidation. The β-oxidation cycles function by shortening the side chains, the first cycle results in the formation of carboxydimethyldecylhydroxychromanol followed by carboxymethyloctylhydroxychromanol. These two metabolites are categorized as long-chain metabolites and they are not excreted in the urine. Some intermediate-chain metabolites that are products of two rounds of β-oxidation are carboxymethylhexylhydroxychromanol and carboxymethylbutylhydroxychromanol. These intermediate-chain metabolites can be found in human feces and urine. The catabolic end-product of tocopherols, as stated before, is CEHC which can be largely found in urine and feces. Two new metabolites have been detected in human and mice feces. These new metabolites are 12'-hydroxychromanol and 11'-hydroxychromanol. Because of their chemistry, it is thought that these metabolites can be the evidence for a ω-1 and ω-2 hydroxylation which leads to an impaired oxidation of 12'-OH followed side-chain truncation. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): The pharmacokinetic profile of tocopherol indicates a longer time of excretion for tocopherols when compared to tocotrienols. The different conjugated metabolites are excreted in the urine or feces depending on the length of their side-chain. Due to their polarity, intermediate-chain metabolites and short-chain metabolites are excreted via urine as glucoside conjugates. A mixture of all the metabolites and precursors can be found in feces. The long-chain metabolites correspond to >60% of the total metabolites in feces. It is estimated that the fecal excretion accounts for even 80% of the administered dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life ranged from 2.44 to 3.02 hours for δ-tocopherol, γ-tocopherol, and β-tocopherol. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance ranged from 0.081 to 0.190 L/h for δ-tocopherol, γ-tocopherol, and β-tocopherol. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Tocopherols are considered as non-toxic but if very high doses are administered, there are reports of hemorrhagic activity. Reproductive and developmental toxicity tests are negative. These negative results were also observed in the analysis of mutagenicity and carcinogenicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): No summary available Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Tolazamide interact?

•Drug A: Bupropion •Drug B: Tolazamide •Severity: MINOR •Description: Tolazamide may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For use as an adjunct to diet to lower the blood glucose in patients with non-insulin dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tolazamide is an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide, may become unresponsive or poorly responsive over time. Alternatively, tolazamide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Sulfonylureas likely bind to ATP-sensitive potassium-channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly and well absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0 to 70%. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0% to 70%. They are excreted principally in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The average biological half-life of the drug is 7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Overdosage of sulfonylureas can produce hypoglycemia. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tolinase •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolazamid Tolazamida Tolazamide Tolazamidum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolazamide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Tolazamide interact? Information: •Drug A: Bupropion •Drug B: Tolazamide •Severity: MINOR •Description: Tolazamide may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For use as an adjunct to diet to lower the blood glucose in patients with non-insulin dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tolazamide is an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide, may become unresponsive or poorly responsive over time. Alternatively, tolazamide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Sulfonylureas likely bind to ATP-sensitive potassium-channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly and well absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0 to 70%. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0% to 70%. They are excreted principally in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The average biological half-life of the drug is 7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Overdosage of sulfonylureas can produce hypoglycemia. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tolinase •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolazamid Tolazamida Tolazamide Tolazamidum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolazamide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Tolbutamide interact?

•Drug A: Bupropion •Drug B: Tolbutamide •Severity: MINOR •Description: Tolbutamide may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For treatment of NIDDM (non-insulin-dependent diabetes mellitus) in conjunction with diet and exercise. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tolbutamide, a first-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Tolbutamide is twice as potent as the related second-generation agent glipizide. Tolbutamide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use insulin efficiently. The pancreas must be able to produce insulin for this drug to work. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Sulfonylureas lower blood glucose in patients with NIDDM by directly stimulating the acute release of insulin from functioning beta cells of pancreatic islet tissue by an unknown process that involves a sulfonylurea receptor (receptor 1) on the beta cell. Sulfonylureas inhibit the ATP-potassium channels on the beta cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Readily absorbed following oral administration. Tolbutamide is detectable in plasma 30-60 minutes following oral administration of a single dose with peak plasma concentrations occurring within 3-5 hours. Absorption is unaltered if taken with food but is increased with high pH. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 95% bound to plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Metabolized in the liver principally via oxidation of the p-methyl group producing the carboxyl metabolite, 1-butyl-3-p-carboxyphenylsulfonylurea. May also be metabolized to hydroxytolbutamide. Tolbutamide does not undergo acetylation like antibacterial sulfonamides as it does not have a p-amino group. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Unchanged drug and metabolites are eliminated in the urine and feces. Approximately 75-85% of a single orally administered dose is excreted in the urine principally as the 1-butyl-3-p-carboxyphenylsulfonylurea within 24 hours. •Half-life (Drug A): 24 hours •Half-life (Drug B): Approximately 7 hours with interindividual variations ranging from 4-25 hours. Tolbutamide has the shortest duration of action, 6-12 hours, of the antidiabetic sulfonylureas. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral, mouse: LD 50 = 2600 mg/kg •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolbutamida Tolbutamide Tolbutamidum Tolylsulfonylbutylurea •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolbutamide is a sulfonylurea used to treat hyperglycemia in patients with type 2 diabetes mellitus.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Tolbutamide interact? Information: •Drug A: Bupropion •Drug B: Tolbutamide •Severity: MINOR •Description: Tolbutamide may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For treatment of NIDDM (non-insulin-dependent diabetes mellitus) in conjunction with diet and exercise. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tolbutamide, a first-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Tolbutamide is twice as potent as the related second-generation agent glipizide. Tolbutamide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use insulin efficiently. The pancreas must be able to produce insulin for this drug to work. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Sulfonylureas lower blood glucose in patients with NIDDM by directly stimulating the acute release of insulin from functioning beta cells of pancreatic islet tissue by an unknown process that involves a sulfonylurea receptor (receptor 1) on the beta cell. Sulfonylureas inhibit the ATP-potassium channels on the beta cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Readily absorbed following oral administration. Tolbutamide is detectable in plasma 30-60 minutes following oral administration of a single dose with peak plasma concentrations occurring within 3-5 hours. Absorption is unaltered if taken with food but is increased with high pH. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 95% bound to plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Metabolized in the liver principally via oxidation of the p-methyl group producing the carboxyl metabolite, 1-butyl-3-p-carboxyphenylsulfonylurea. May also be metabolized to hydroxytolbutamide. Tolbutamide does not undergo acetylation like antibacterial sulfonamides as it does not have a p-amino group. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Unchanged drug and metabolites are eliminated in the urine and feces. Approximately 75-85% of a single orally administered dose is excreted in the urine principally as the 1-butyl-3-p-carboxyphenylsulfonylurea within 24 hours. •Half-life (Drug A): 24 hours •Half-life (Drug B): Approximately 7 hours with interindividual variations ranging from 4-25 hours. Tolbutamide has the shortest duration of action, 6-12 hours, of the antidiabetic sulfonylureas. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral, mouse: LD 50 = 2600 mg/kg •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolbutamida Tolbutamide Tolbutamidum Tolylsulfonylbutylurea •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolbutamide is a sulfonylurea used to treat hyperglycemia in patients with type 2 diabetes mellitus. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Tolcapone interact?

•Drug A: Bupropion •Drug B: Tolcapone •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Bupropion is combined with Tolcapone. •Extended Description: Despite the fact that these drugs are sometimes used in combination to treat depression in Parkinson's disease3, the administration of bupropion with anti-Parkinson drugs may lead to central nervous system toxicity. Bupropion is considered a norepinephrine-dopamine reuptake inhibitor, is found to occupy the DAT dopamine transporter, and acts as a dopamine agonist. Additive effects of these dopaminergic drugs may produce excess dopaminergic activity. Agitation, restlessness, tremor, ataxia, gait disturbance, and dizziness are some examples of effects that may occur from concurrent administration. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Used as an adjunct to levodopa/carbidopa therapy for the symptomatic treatment of Parkinson's Disease. This drug is generally reserved for patients with parkinsonian syndrome receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to or are not candidates for other adjunctive therapies. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tolcapone is a potent, selective, and reversible inhibitor of catechol-O-methyltransferase (COMT). In humans, COMT is distributed throughout various organs. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. COMT is responsible for the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa, resulting in an increase in plasma levodopa concentrations. The inhibition of COMT also causes a reduction in circulating 3-OMD as a result of decreased peripheral metabolism of levodopa. This may lead to an increase distribution of levodopa into the CNS through the reduction of its competitive substrate, 3-OMD, for transport mechanisms. Sustained levodopa concentrations presumably result in more consistent dopaminergic stimulation, resulting in greater reduction in the manifestations of parkinsonian syndrome. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed (absolute bioavailability is about 65%) •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 9 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): > 99.9% (to serum albumin) •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The main metabolic pathway of tolcapone is glucuronidation •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile. •Half-life (Drug A): 24 hours •Half-life (Drug B): 2-3.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 7 L/h •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD 50 = 1600 mg/kg (Orally in rats) •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tasmar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolcapon Tolcapona Tolcapone Tolcaponum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor used as adjunct therapy in the symptomatic management of idiopathic Parkinson's disease.

Despite the fact that these drugs are sometimes used in combination to treat depression in Parkinson's disease3, the administration of bupropion with anti-Parkinson drugs may lead to central nervous system toxicity. Bupropion is considered a norepinephrine-dopamine reuptake inhibitor, is found to occupy the DAT dopamine transporter, and acts as a dopamine agonist. Additive effects of these dopaminergic drugs may produce excess dopaminergic activity. Agitation, restlessness, tremor, ataxia, gait disturbance, and dizziness are some examples of effects that may occur from concurrent administration. The severity of the interaction is moderate.

Question: Does Bupropion and Tolcapone interact? Information: •Drug A: Bupropion •Drug B: Tolcapone •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Bupropion is combined with Tolcapone. •Extended Description: Despite the fact that these drugs are sometimes used in combination to treat depression in Parkinson's disease3, the administration of bupropion with anti-Parkinson drugs may lead to central nervous system toxicity. Bupropion is considered a norepinephrine-dopamine reuptake inhibitor, is found to occupy the DAT dopamine transporter, and acts as a dopamine agonist. Additive effects of these dopaminergic drugs may produce excess dopaminergic activity. Agitation, restlessness, tremor, ataxia, gait disturbance, and dizziness are some examples of effects that may occur from concurrent administration. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Used as an adjunct to levodopa/carbidopa therapy for the symptomatic treatment of Parkinson's Disease. This drug is generally reserved for patients with parkinsonian syndrome receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to or are not candidates for other adjunctive therapies. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tolcapone is a potent, selective, and reversible inhibitor of catechol-O-methyltransferase (COMT). In humans, COMT is distributed throughout various organs. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. COMT is responsible for the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa, resulting in an increase in plasma levodopa concentrations. The inhibition of COMT also causes a reduction in circulating 3-OMD as a result of decreased peripheral metabolism of levodopa. This may lead to an increase distribution of levodopa into the CNS through the reduction of its competitive substrate, 3-OMD, for transport mechanisms. Sustained levodopa concentrations presumably result in more consistent dopaminergic stimulation, resulting in greater reduction in the manifestations of parkinsonian syndrome. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed (absolute bioavailability is about 65%) •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 9 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): > 99.9% (to serum albumin) •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The main metabolic pathway of tolcapone is glucuronidation •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile. •Half-life (Drug A): 24 hours •Half-life (Drug B): 2-3.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 7 L/h •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD 50 = 1600 mg/kg (Orally in rats) •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tasmar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolcapon Tolcapona Tolcapone Tolcaponum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor used as adjunct therapy in the symptomatic management of idiopathic Parkinson's disease. Output: Despite the fact that these drugs are sometimes used in combination to treat depression in Parkinson's disease3, the administration of bupropion with anti-Parkinson drugs may lead to central nervous system toxicity. Bupropion is considered a norepinephrine-dopamine reuptake inhibitor, is found to occupy the DAT dopamine transporter, and acts as a dopamine agonist. Additive effects of these dopaminergic drugs may produce excess dopaminergic activity. Agitation, restlessness, tremor, ataxia, gait disturbance, and dizziness are some examples of effects that may occur from concurrent administration. The severity of the interaction is moderate.

Does Bupropion and Tolfenamic acid interact?

•Drug A: Bupropion •Drug B: Tolfenamic acid •Severity: MINOR •Description: Tolfenamic acid may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): In the information for tolfenamic acid, it is stated that this drug, being an NSAID, is effective in treating the pain associated with the acute attack of migraines in adults. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Studies have shown that tolfenamic acid presents a non-dose dependent partial inhibition of irritant-induced temperature rise as well as a dose-dependent inhibition of skin edema. By studying its NSAID properties more closely, it was noted a dose-related inhibition of serum thromboxane which indicated the inhibition of COX-1. In the same line, there was noted a inhibition of prostaglandin E2 synthesis which marks a related COX-2 inhibition. The maximal inhibition of thromboxane was greater than 80% as well as is proven to be a potent prostaglandin E inhibitor. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tolfenamic acid inhibits the biosynthesis of prostaglandins, and it also presents inhibitory actions on the prostaglandin receptors. As commonly thought, the mechanism of action of tolfenamic acid is based on the major mechanism of NSAIDs which consists of the inhibition of COX-1 and COX-2 pathways to inhibit prostaglandin secretion and action and thus, to exert its anti-inflammatory and pain-blocking action. Nonetheless, some report currently indicates that tolfenamic acid inhibits leukotriene B4 chemotaxis of human polymorphonuclear leukocytes leading to an inhibition of even 25% of the chemotactic response. This activity is a not ligand specific additional anti-inflammatory mechanism of tolfenamic acid. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Tolfenamic acid pharmacokinetic is marked by a short tmax of 0.94-2.04 h. It also presented a linear pharmacokinetic profile with an AUC from 13-50 mcg/ml.h if administered in a dose of 2-8 mg/kg respectively. The oral absorption is delayed and it gives a mean lag-time to absorption of 32 min. The peak plasma concentration of 11.1 mcg/ml. The bioavailability of tolfenamic acid is around 75%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution is of 1.79-3.2 L/kg. When tested intravenously, the reported steady-state volume of distribution was 0.33 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tolfenamic acid presents high protein binding properties reaching 99.7% of the administered dose. Studies have studied the changes in protein binding depending on the presence of certain disorders that modify the dialysis equilibrium. These studies verify that modifications in blood creatinine, urea and bilirubin can significantly alter the concentration of unbound tolfenamic acid. The main binding structure is predicted to be related to lipid membrane structures. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The first pass metabolism accounts for 20% of the administered dose of tolfenamic acid. Urine metabolite studies have demonstrated the identification of five metabolites from which three of them are monohydroxylated, one is monohydroxylated and hydroxylated and one last metabolite that presented and oxidized methyl group to form a carboxyl group. Two of these hydroxylated metabolites are N-(2-hydroxymethyl-3-chlorophenyl)-anthranilic acid and N-(2-hydroxymethyl-3-chloro-4-hydroxyphenyl)-anthranilic acid. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tolfenamic acid is cleared relatively fast and it undergoes by hepatic metabolism where the produced metabolites are renally cleared as glucuronic acid conjugates. Most of the elimination occurs by extrarenal mechanisms in which the unchanged drug together with its glucuronide in urine accounts for only 8.8% of the administered dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): The estimated half-life of tolfenamic acid is 8.01-13.50 hours. When tested intravenously, the reported half-life was 6.1h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The estimated clearance rate of tolfenamic acid is 0.142-0.175 L.h/kg. When tested intravenously, the reported clearance rate was 72.4 ml.h/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Tolfenamic acid has a relatively low acute toxicity with LD50 values in 200-1000 mg/kg. The metabolites of tolfenamic acid are reported to have an even less important toxicity. Some of the expected toxicity is related to the presence of gastrointestinal effects such as gut ulceration and renal papillitis. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): No summary available

The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Tolfenamic acid interact? Information: •Drug A: Bupropion •Drug B: Tolfenamic acid •Severity: MINOR •Description: Tolfenamic acid may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): In the information for tolfenamic acid, it is stated that this drug, being an NSAID, is effective in treating the pain associated with the acute attack of migraines in adults. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Studies have shown that tolfenamic acid presents a non-dose dependent partial inhibition of irritant-induced temperature rise as well as a dose-dependent inhibition of skin edema. By studying its NSAID properties more closely, it was noted a dose-related inhibition of serum thromboxane which indicated the inhibition of COX-1. In the same line, there was noted a inhibition of prostaglandin E2 synthesis which marks a related COX-2 inhibition. The maximal inhibition of thromboxane was greater than 80% as well as is proven to be a potent prostaglandin E inhibitor. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tolfenamic acid inhibits the biosynthesis of prostaglandins, and it also presents inhibitory actions on the prostaglandin receptors. As commonly thought, the mechanism of action of tolfenamic acid is based on the major mechanism of NSAIDs which consists of the inhibition of COX-1 and COX-2 pathways to inhibit prostaglandin secretion and action and thus, to exert its anti-inflammatory and pain-blocking action. Nonetheless, some report currently indicates that tolfenamic acid inhibits leukotriene B4 chemotaxis of human polymorphonuclear leukocytes leading to an inhibition of even 25% of the chemotactic response. This activity is a not ligand specific additional anti-inflammatory mechanism of tolfenamic acid. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Tolfenamic acid pharmacokinetic is marked by a short tmax of 0.94-2.04 h. It also presented a linear pharmacokinetic profile with an AUC from 13-50 mcg/ml.h if administered in a dose of 2-8 mg/kg respectively. The oral absorption is delayed and it gives a mean lag-time to absorption of 32 min. The peak plasma concentration of 11.1 mcg/ml. The bioavailability of tolfenamic acid is around 75%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution is of 1.79-3.2 L/kg. When tested intravenously, the reported steady-state volume of distribution was 0.33 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Tolfenamic acid presents high protein binding properties reaching 99.7% of the administered dose. Studies have studied the changes in protein binding depending on the presence of certain disorders that modify the dialysis equilibrium. These studies verify that modifications in blood creatinine, urea and bilirubin can significantly alter the concentration of unbound tolfenamic acid. The main binding structure is predicted to be related to lipid membrane structures. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The first pass metabolism accounts for 20% of the administered dose of tolfenamic acid. Urine metabolite studies have demonstrated the identification of five metabolites from which three of them are monohydroxylated, one is monohydroxylated and hydroxylated and one last metabolite that presented and oxidized methyl group to form a carboxyl group. Two of these hydroxylated metabolites are N-(2-hydroxymethyl-3-chlorophenyl)-anthranilic acid and N-(2-hydroxymethyl-3-chloro-4-hydroxyphenyl)-anthranilic acid. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tolfenamic acid is cleared relatively fast and it undergoes by hepatic metabolism where the produced metabolites are renally cleared as glucuronic acid conjugates. Most of the elimination occurs by extrarenal mechanisms in which the unchanged drug together with its glucuronide in urine accounts for only 8.8% of the administered dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): The estimated half-life of tolfenamic acid is 8.01-13.50 hours. When tested intravenously, the reported half-life was 6.1h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The estimated clearance rate of tolfenamic acid is 0.142-0.175 L.h/kg. When tested intravenously, the reported clearance rate was 72.4 ml.h/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Tolfenamic acid has a relatively low acute toxicity with LD50 values in 200-1000 mg/kg. The metabolites of tolfenamic acid are reported to have an even less important toxicity. Some of the expected toxicity is related to the presence of gastrointestinal effects such as gut ulceration and renal papillitis. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): No summary available Output: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Does Bupropion and Tolmetin interact?

•Drug A: Bupropion •Drug B: Tolmetin •Severity: MINOR •Description: Tolmetin may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, including the treatment of acute flares long-term management. Also for treatment of juvenile rheumatoid arthritis. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tolmetin is a nonsteroidal anti-inflammatory agent. Studies in animals have shown tolmetin to possess anti-inflammatory, analgesic and antipyretic activity. In the rat, tolmetin prevents the development of experimentally induced polyarthritis and also decreases established inflammation. In patients with either rheumatoid arthritis or osteaoarthritis, tolmetin is as effective as aspirin and indomethacin in controlling disease activity, but the frequency of the milder gastrointestinal adverse effects and tinnitus was less than in aspirin-treated patients, and the incidence of central nervous system adverse effects was less than in indomethacin-treated patients. In patients with juvenile rheumatoid arthritis, tolmetin is as effective as aspirin in controlling disease activity, with a similar incidence of adverse reactions. tolmetin has produced additional therapeutic benefit when added to a regimen of gold salts and, to a lesser extent, with corticosteroids. Tolmetin should not be used in conjunction with salicylates since greater benefit from the combination is not likely, but the potential for adverse reactions is increased. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mode of action of tolmetin is not known. However, studies in laboratory animals and man have demonstrated that the anti-inflammatory action of tolmetin is not due to pituitary-adrenal stimulation. Tolmetin inhibits prostaglandin synthetase in vitro and lowers the plasma level of prostaglandin E in man. This reduction in prostaglandin synthesis may be responsible for the anti-inflammatory action. Tolmetin does not appear to alter the course of the underlying disease in man. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly and almost completely absorbed with peak plasma levels being reached within 30-60 minutes after an oral therapeutic dose. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Essentially all of the administered dose is recovered in the urine in 24 hours either as an inactive oxidative metabolite or as conjugates of tolmetin. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): Biphasic elimination from the plasma consisting of a rapid phase with a half-life of one to 2 hours followed by a slower phase with a half-life of about 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolmetin Tolmetina Tolmétine Tolmetino Tolmetinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolmetin is an NSAID used to treat acute flares of various painful conditions and used for the long term management of osteoarthritis, rheumatoid arthritis, and juvenile arthritis.

The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Tolmetin interact? Information: •Drug A: Bupropion •Drug B: Tolmetin •Severity: MINOR •Description: Tolmetin may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, including the treatment of acute flares long-term management. Also for treatment of juvenile rheumatoid arthritis. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tolmetin is a nonsteroidal anti-inflammatory agent. Studies in animals have shown tolmetin to possess anti-inflammatory, analgesic and antipyretic activity. In the rat, tolmetin prevents the development of experimentally induced polyarthritis and also decreases established inflammation. In patients with either rheumatoid arthritis or osteaoarthritis, tolmetin is as effective as aspirin and indomethacin in controlling disease activity, but the frequency of the milder gastrointestinal adverse effects and tinnitus was less than in aspirin-treated patients, and the incidence of central nervous system adverse effects was less than in indomethacin-treated patients. In patients with juvenile rheumatoid arthritis, tolmetin is as effective as aspirin in controlling disease activity, with a similar incidence of adverse reactions. tolmetin has produced additional therapeutic benefit when added to a regimen of gold salts and, to a lesser extent, with corticosteroids. Tolmetin should not be used in conjunction with salicylates since greater benefit from the combination is not likely, but the potential for adverse reactions is increased. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mode of action of tolmetin is not known. However, studies in laboratory animals and man have demonstrated that the anti-inflammatory action of tolmetin is not due to pituitary-adrenal stimulation. Tolmetin inhibits prostaglandin synthetase in vitro and lowers the plasma level of prostaglandin E in man. This reduction in prostaglandin synthesis may be responsible for the anti-inflammatory action. Tolmetin does not appear to alter the course of the underlying disease in man. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly and almost completely absorbed with peak plasma levels being reached within 30-60 minutes after an oral therapeutic dose. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Essentially all of the administered dose is recovered in the urine in 24 hours either as an inactive oxidative metabolite or as conjugates of tolmetin. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): Biphasic elimination from the plasma consisting of a rapid phase with a half-life of one to 2 hours followed by a slower phase with a half-life of about 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolmetin Tolmetina Tolmétine Tolmetino Tolmetinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolmetin is an NSAID used to treat acute flares of various painful conditions and used for the long term management of osteoarthritis, rheumatoid arthritis, and juvenile arthritis. Output: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Does Bupropion and Tolterodine interact?

•Drug A: Bupropion •Drug B: Tolterodine •Severity: MAJOR •Description: The metabolism of Tolterodine can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of overactive bladder (with symptoms of urinary frequency, urgency, or urge incontinence). •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels. Tolterodine has a pronounced effect on bladder function. The main effects of tolterodine are an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure, consistent with an antimuscarinic action on the lower urinary tract. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Both tolterodine and its active metabolite, 5-hydroxymethyltolterodine, act as competitive antagonists at muscarinic receptors. This antagonism results in inhibition of bladder contraction, decrease in detrusor pressure, and an incomplete emptying of the bladder. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 113 ± 26.7 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 96.3%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following administration of a 5-mg oral dose of 14C-tolterodine solution to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in feces in 7 days. •Half-life (Drug A): 24 hours •Half-life (Drug B): 1.9-3.7 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Detrol, Detrusitol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolterodina Tolterodine Tolterodinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolterodine is a muscarinic receptor antagonist used to treat overactive bladder with urinary incontinence, urgency, and frequency.

The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Tolterodine interact? Information: •Drug A: Bupropion •Drug B: Tolterodine •Severity: MAJOR •Description: The metabolism of Tolterodine can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of overactive bladder (with symptoms of urinary frequency, urgency, or urge incontinence). •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels. Tolterodine has a pronounced effect on bladder function. The main effects of tolterodine are an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure, consistent with an antimuscarinic action on the lower urinary tract. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Both tolterodine and its active metabolite, 5-hydroxymethyltolterodine, act as competitive antagonists at muscarinic receptors. This antagonism results in inhibition of bladder contraction, decrease in detrusor pressure, and an incomplete emptying of the bladder. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 113 ± 26.7 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 96.3%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following administration of a 5-mg oral dose of 14C-tolterodine solution to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in feces in 7 days. •Half-life (Drug A): 24 hours •Half-life (Drug B): 1.9-3.7 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Detrol, Detrusitol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolterodina Tolterodine Tolterodinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolterodine is a muscarinic receptor antagonist used to treat overactive bladder with urinary incontinence, urgency, and frequency. Output: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Tolvaptan interact?

•Drug A: Bupropion •Drug B: Tolvaptan •Severity: MODERATE •Description: Tolvaptan may increase the excretion rate of Bupropion which could result in a lower serum level and potentially a reduction in efficacy. •Extended Description: The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and cirrhosis. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan. Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours. The magnitude of serum sodium and osmolality change increases with escalating doses. Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan. The affinity for V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls thus preventing water absorption. This action ultimately results in an increase in urine volume, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Tmax, Healthy subjects: 2 - 4 hours; Cmax, Healthy subjects, 30 mg: 374 ng/mL; Cmax, Healthy subjects, 90 mg: 418 ng/mL; Cmax, heart failure patients, 30 mg: 460 ng/mL; Cmax, heart failure patients, 90 mg: 723 ng/mL; AUC(0-24 hours), 60 mg: 3.71 μg·h/mL; AUC(∞), 60 mg: 4.55 μg·h/mL; The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Food does not impact the bioavailability of tolvaptan. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Healthy subjects: 3L/kg; slightly higher in heart failure patients. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 99% bound •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Metabolism exclusively by CYP3A4 enzyme in the liver. Metabolites are inactive. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Fecal- very little renal elimination (<1% is excreted unchanged in the urine) •Half-life (Drug A): 24 hours •Half-life (Drug B): Terminal half life, oral dose = 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 4 mL/min/kg (post-oral dosing). •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Jinarc, Jynarque 45/15 Carton, Samsca •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolvaptan is a selective vasopressin V2-receptor antagonist to slow kidney function decline in patients at risk for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Also used to treat hypervolemic and euvolemic hyponatremia.

The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. The severity of the interaction is moderate.

Question: Does Bupropion and Tolvaptan interact? Information: •Drug A: Bupropion •Drug B: Tolvaptan •Severity: MODERATE •Description: Tolvaptan may increase the excretion rate of Bupropion which could result in a lower serum level and potentially a reduction in efficacy. •Extended Description: The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and cirrhosis. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan. Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours. The magnitude of serum sodium and osmolality change increases with escalating doses. Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan. The affinity for V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls thus preventing water absorption. This action ultimately results in an increase in urine volume, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Tmax, Healthy subjects: 2 - 4 hours; Cmax, Healthy subjects, 30 mg: 374 ng/mL; Cmax, Healthy subjects, 90 mg: 418 ng/mL; Cmax, heart failure patients, 30 mg: 460 ng/mL; Cmax, heart failure patients, 90 mg: 723 ng/mL; AUC(0-24 hours), 60 mg: 3.71 μg·h/mL; AUC(∞), 60 mg: 4.55 μg·h/mL; The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Food does not impact the bioavailability of tolvaptan. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Healthy subjects: 3L/kg; slightly higher in heart failure patients. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 99% bound •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Metabolism exclusively by CYP3A4 enzyme in the liver. Metabolites are inactive. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Fecal- very little renal elimination (<1% is excreted unchanged in the urine) •Half-life (Drug A): 24 hours •Half-life (Drug B): Terminal half life, oral dose = 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 4 mL/min/kg (post-oral dosing). •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Jinarc, Jynarque 45/15 Carton, Samsca •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tolvaptan is a selective vasopressin V2-receptor antagonist to slow kidney function decline in patients at risk for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Also used to treat hypervolemic and euvolemic hyponatremia. Output: The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. The severity of the interaction is moderate.

Does Bupropion and Topiramate interact?

•Drug A: Bupropion •Drug B: Topiramate •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Topiramate is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Topiramate is indicated for the following conditions: 1)Monotherapy for partial onset or primary generalized tonic-clonic seizures for patients 2 years of age and above 2)Adjunctive therapy for partial onset seizures or primary generalized tonic-clonic seizures for both adult and pediatric patients above 2 years old 3)Adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in patients above 2 years of age 4)Prophylaxis of migraine in children 12 years of age and older and adults. Topiramate is also used off-label as an adjunct therapy for weight management and for mood disorders. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Topiramate prevents the occurrence of seizures and prevents migraine symptoms by reducing neural pathway excitability. It is important to note that this drug may cause metabolic acidosis, mood changes, suicidal thoughts and attempts, as well as kidney stones. When topiramate is combined with valproic acid, it is known to cause hypothermia. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): A seizure is an abnormal and unregulated electrical discharge occurring in the brain. This leads to transient interruption in brain function, manifested by reduced alertness, abnormal sensations, and focal involuntary movements or convulsions. Several types of seizures exist, with common types including tonic-clonic seizures and partial onset seizures. The exact mechanisms by which topiramate exerts pharmacological actions on seizures and migraines are currently not fully characterized. Several properties of this drug, however, are likely to contribute to its therapeutic effects. Topiramate has been observed to exert actions on voltage-dependent sodium channels, GABA receptors, and glutamate receptors. Topiramate stimulates GABA-A receptor activity at brain non-benzodiazepine receptor sites and reduces glutamate activity at both AMPA and kainate receptors. Normally, GABA-A receptors are inhibitory and glutaminergic receptors are stimulatory for neuronal activity. By increasing GABA activity and inhibiting glutamate activity, topiramate blocks neuronal excitability, preventing seizures and migraines. Additionally, it blocks the voltage-dependent sodium channels, further blocking seizure activity. Topiramate has been shown to inhibit various carbonic anhydrase isozymes, but the clinical significance of this is unknown at this time. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After a 400mg dose in one clinical trial, topiramate reached maximal concentrations within 1.8-4.3 hours and ranged from 1.73-28.7 ug/mL. Food did not significantly affect the extent of absorption, despite delaying time to peak concentration. In patients with normal creatinine clearance, steady state concentrations are reached within 4 days. The bioavailability of topiramate in tablet form is about 80% compared to a topiramate solution. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean apparent volume of distribution of topiramate ranges from 0.6-0.8 L/kg when doses of 100mg to 1200mg are given. Topiramate readily crosses the blood-brain barrier. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Topiramate is not highly bound to plasma proteins, with an estimated plasma protein binding of 9-17% according to some studies. The FDA label indicates that the protein binding of topiramate is 15-41%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The metabolites of topiramate are not known to be active. The metabolism of topiramate is characterized by reactions of glucuronidation, hydroxylation and hydrolysis that lead to the production of six minor metabolites. Some of topiramate's metabolites include 2,3-desisopropylidene topiramate, 4,5-desisopropylidene topiramate, 9-hydroxy topiramate, and 10-hydroxy topiramate. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Topiramate is mainly eliminated through the kidneys. About 70-80% of the eliminated dose is found unchanged in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life is reported to be in the range of 19-23 hours. If topiramate is given with enzyme-inducers, the half-life can be reduced to 12-15 hours because of increased metabolism. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean oral plasma clearance of topiramate ranges from 22-36 mL/min while the renal clearance is 17-18 mL/min, according to one pharmacokinetic study. The FDA label for topiramate indicates a similar oral plasma clearance of approximately 20 to 30 mL/min in adults. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The LD50 of intraperitoneal topiramate in the rat is above 1500 mg/kg. Overdose information In a study of 4 healthy adult women taking topiramate, the severity of clinical effects following an overdose ranged from asymptomatic to severe, with no deaths reported. According to the FDA prescribing information for topiramate, an overdose may cause hypotension, severe metabolic acidosis, coma, abdominal pain, visual disturbances, convulsions, drowsiness, speech abnormalities, impaired mentation and coordination, stupor, agitation, dizziness, as well as depression. In the case of a recent ingestion of topiramate, the stomach contents should be emptied through the induction of emesis or gastric lavage. Offer supportive treatment, including activated charcoal and hemodialysis. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Eprontia, Qsymia, Qudexy, Topamax, Trokendi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tipiramate Tipiramato Topiramate Topiramato Topiramatum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Topiramate is an anticonvulsant drug used in the control of epilepsy and in the prophylaxis and treatment of migraines.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Topiramate interact? Information: •Drug A: Bupropion •Drug B: Topiramate •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Topiramate is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Topiramate is indicated for the following conditions: 1)Monotherapy for partial onset or primary generalized tonic-clonic seizures for patients 2 years of age and above 2)Adjunctive therapy for partial onset seizures or primary generalized tonic-clonic seizures for both adult and pediatric patients above 2 years old 3)Adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in patients above 2 years of age 4)Prophylaxis of migraine in children 12 years of age and older and adults. Topiramate is also used off-label as an adjunct therapy for weight management and for mood disorders. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Topiramate prevents the occurrence of seizures and prevents migraine symptoms by reducing neural pathway excitability. It is important to note that this drug may cause metabolic acidosis, mood changes, suicidal thoughts and attempts, as well as kidney stones. When topiramate is combined with valproic acid, it is known to cause hypothermia. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): A seizure is an abnormal and unregulated electrical discharge occurring in the brain. This leads to transient interruption in brain function, manifested by reduced alertness, abnormal sensations, and focal involuntary movements or convulsions. Several types of seizures exist, with common types including tonic-clonic seizures and partial onset seizures. The exact mechanisms by which topiramate exerts pharmacological actions on seizures and migraines are currently not fully characterized. Several properties of this drug, however, are likely to contribute to its therapeutic effects. Topiramate has been observed to exert actions on voltage-dependent sodium channels, GABA receptors, and glutamate receptors. Topiramate stimulates GABA-A receptor activity at brain non-benzodiazepine receptor sites and reduces glutamate activity at both AMPA and kainate receptors. Normally, GABA-A receptors are inhibitory and glutaminergic receptors are stimulatory for neuronal activity. By increasing GABA activity and inhibiting glutamate activity, topiramate blocks neuronal excitability, preventing seizures and migraines. Additionally, it blocks the voltage-dependent sodium channels, further blocking seizure activity. Topiramate has been shown to inhibit various carbonic anhydrase isozymes, but the clinical significance of this is unknown at this time. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After a 400mg dose in one clinical trial, topiramate reached maximal concentrations within 1.8-4.3 hours and ranged from 1.73-28.7 ug/mL. Food did not significantly affect the extent of absorption, despite delaying time to peak concentration. In patients with normal creatinine clearance, steady state concentrations are reached within 4 days. The bioavailability of topiramate in tablet form is about 80% compared to a topiramate solution. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean apparent volume of distribution of topiramate ranges from 0.6-0.8 L/kg when doses of 100mg to 1200mg are given. Topiramate readily crosses the blood-brain barrier. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Topiramate is not highly bound to plasma proteins, with an estimated plasma protein binding of 9-17% according to some studies. The FDA label indicates that the protein binding of topiramate is 15-41%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The metabolites of topiramate are not known to be active. The metabolism of topiramate is characterized by reactions of glucuronidation, hydroxylation and hydrolysis that lead to the production of six minor metabolites. Some of topiramate's metabolites include 2,3-desisopropylidene topiramate, 4,5-desisopropylidene topiramate, 9-hydroxy topiramate, and 10-hydroxy topiramate. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Topiramate is mainly eliminated through the kidneys. About 70-80% of the eliminated dose is found unchanged in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life is reported to be in the range of 19-23 hours. If topiramate is given with enzyme-inducers, the half-life can be reduced to 12-15 hours because of increased metabolism. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean oral plasma clearance of topiramate ranges from 22-36 mL/min while the renal clearance is 17-18 mL/min, according to one pharmacokinetic study. The FDA label for topiramate indicates a similar oral plasma clearance of approximately 20 to 30 mL/min in adults. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The LD50 of intraperitoneal topiramate in the rat is above 1500 mg/kg. Overdose information In a study of 4 healthy adult women taking topiramate, the severity of clinical effects following an overdose ranged from asymptomatic to severe, with no deaths reported. According to the FDA prescribing information for topiramate, an overdose may cause hypotension, severe metabolic acidosis, coma, abdominal pain, visual disturbances, convulsions, drowsiness, speech abnormalities, impaired mentation and coordination, stupor, agitation, dizziness, as well as depression. In the case of a recent ingestion of topiramate, the stomach contents should be emptied through the induction of emesis or gastric lavage. Offer supportive treatment, including activated charcoal and hemodialysis. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Eprontia, Qsymia, Qudexy, Topamax, Trokendi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tipiramate Tipiramato Topiramate Topiramato Topiramatum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Topiramate is an anticonvulsant drug used in the control of epilepsy and in the prophylaxis and treatment of migraines. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Topotecan interact?

•Drug A: Bupropion •Drug B: Topotecan •Severity: MINOR •Description: Topotecan may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 35% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%. •Half-life (Drug A): 24 hours •Half-life (Drug B): 2-3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The primary anticipated complication of overdosage would consist of bone marrow suppression. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Hycamtin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Topotecan Topotecane Topotecanum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Topotecan is an antineoplastic agent used to treat ovarian cancer, small cell lung cancer, or cervical cancer.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Topotecan interact? Information: •Drug A: Bupropion •Drug B: Topotecan •Severity: MINOR •Description: Topotecan may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 35% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%. •Half-life (Drug A): 24 hours •Half-life (Drug B): 2-3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The primary anticipated complication of overdosage would consist of bone marrow suppression. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Hycamtin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Topotecan Topotecane Topotecanum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Topotecan is an antineoplastic agent used to treat ovarian cancer, small cell lung cancer, or cervical cancer. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Torasemide interact?

•Drug A: Bupropion •Drug B: Torasemide •Severity: MODERATE •Description: Torasemide may increase the excretion rate of Bupropion which could result in a lower serum level and potentially a reduction in efficacy. •Extended Description: The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Torasemide is indicated for the treatment of edema associated with congestive heart failure, renal or hepatic diseases. From this condition, it has been observed that torasemide is very effective in cases of kidney failure. As well, torasemide is approved to be used as an antihypertensive agent either alone or in combination with other antihypertensives. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): It is widely known that administration of torasemide can attenuate renal injury and reduce the severity of acute renal failure. This effect is obtained by increasing urine output and hence, facilitating fluid, acid-base and potassium control. This effect is obtained by the increase in the excretion of urinary sodium and chloride. Several reports have indicated that torasemide presents a long-lasting diuresis and less potassium excretion which can be explained by the effect that torasemide has on the renin-angiotensin-aldosterone system. This effect is very similar to the effect observed with the administration of combination therapy with furosemide and spironolactone and it is characterized by a decrease in plasma brain natriuretic peptide and improved measurements of left ventricular function. Above the aforementioned effect, torasemide presents a dual effect.in which the inhibition of aldosterone which donates torasemide with a potassium-sparing action. Torasemide has been shown to reduce extracellular fluid volume and blood pressure in hypertensive patients suffering from chronic kidney disease. As well, some reports have indicated that torasemide can reduce myocardial fibrosis by reducing the collagen accumulation. This effect is suggested to be related to the decrease in aldosterone which in order has been shown to reduce the production of the enzyme procollagen type I carboxy-terminal proteinase which is known to be overexpressed in heart failure patients. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): As mentioned above, torasemide is part of the loop diuretics and thus, it acts by reducing the oxygen demand in the medullary thick ascending loop of Henle by inhibiting the Na+/K+/Cl- pump on the luminal cell membrane surface. This action is obtained by the binding of torasemide to a chloride ion-binding site of the transport molecule. Torasemide is known to have an effect in the renin-angiotensin-aldosterone system by inhibiting the downstream cascade after the activation of angiotensin II. This inhibition will produce a secondary effect marked by the reduction of the expression of aldosterone synthase, TGF-B1 and thromboxane A2 and a reduction on the aldosterone receptor binding. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Torasemide is the diuretic with the highest oral bioavailability even in advanced stages of chronic kidney disease. This bioavailability tends to be higher than 80% regardless of the patient condition. The maximal serum concentration is reported to be of 1 hour and the absorption parameters are not affected by its use concomitantly with food. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of torasemide is 0.2 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Torasemide is found to be highly bound to plasma proteins, representing over 99% of the administered dose. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Torasemide is extensively metabolized in the liver and only 20% of the dose remains unchanged and it is recovered in the urine. Metabolized via the hepatic CYP2C8 and CYP2C9 mainly by reactions of hydroxylation, oxidation and reduction to 5 metabolites. The major metabolite, M5, is pharmacologically inactive. There are 2 minor metabolites, M1, possessing one-tenth the activity of torasemide, and M3, equal in activity to torasemide. Overall, torasemide appears to account for 80% of the total diuretic activity, while metabolites M1 and M3 account for 9% and 11%, respectively. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Torasemide is mainly hepatically processed and excreted in the feces from which about 70-80% of the administered dose is excreted by this pathway. On the other hand, about 20-30% of the administered dose is found in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The average half-life of torasemide is 3.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance rate of torasemide is considerably reduced by the presence of renal disorders. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD50 of torasemide in the rat is 5 g/kg. When overdose occurs, there is a marked diuresis with the danger of loss of fluid and electrolytes which has been seen to lead to somnolence, confusion, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, hemoconcentration dehydration and circulatory collapse. This effects can include some gastrointestinal disturbances. There is no increase in tumor incidence with torasemide and it is proven to not be mutagenic, not fetotoxic or teratogenic. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Demadex, Soaanz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Torasemida Torasemide Torasémide Torasemidum Torsemide •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Torasemide is a diuretic used to treat hypertension and edema associated with heart failure, renal failure, or liver disease.

The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. The severity of the interaction is moderate.

Question: Does Bupropion and Torasemide interact? Information: •Drug A: Bupropion •Drug B: Torasemide •Severity: MODERATE •Description: Torasemide may increase the excretion rate of Bupropion which could result in a lower serum level and potentially a reduction in efficacy. •Extended Description: The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Torasemide is indicated for the treatment of edema associated with congestive heart failure, renal or hepatic diseases. From this condition, it has been observed that torasemide is very effective in cases of kidney failure. As well, torasemide is approved to be used as an antihypertensive agent either alone or in combination with other antihypertensives. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): It is widely known that administration of torasemide can attenuate renal injury and reduce the severity of acute renal failure. This effect is obtained by increasing urine output and hence, facilitating fluid, acid-base and potassium control. This effect is obtained by the increase in the excretion of urinary sodium and chloride. Several reports have indicated that torasemide presents a long-lasting diuresis and less potassium excretion which can be explained by the effect that torasemide has on the renin-angiotensin-aldosterone system. This effect is very similar to the effect observed with the administration of combination therapy with furosemide and spironolactone and it is characterized by a decrease in plasma brain natriuretic peptide and improved measurements of left ventricular function. Above the aforementioned effect, torasemide presents a dual effect.in which the inhibition of aldosterone which donates torasemide with a potassium-sparing action. Torasemide has been shown to reduce extracellular fluid volume and blood pressure in hypertensive patients suffering from chronic kidney disease. As well, some reports have indicated that torasemide can reduce myocardial fibrosis by reducing the collagen accumulation. This effect is suggested to be related to the decrease in aldosterone which in order has been shown to reduce the production of the enzyme procollagen type I carboxy-terminal proteinase which is known to be overexpressed in heart failure patients. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): As mentioned above, torasemide is part of the loop diuretics and thus, it acts by reducing the oxygen demand in the medullary thick ascending loop of Henle by inhibiting the Na+/K+/Cl- pump on the luminal cell membrane surface. This action is obtained by the binding of torasemide to a chloride ion-binding site of the transport molecule. Torasemide is known to have an effect in the renin-angiotensin-aldosterone system by inhibiting the downstream cascade after the activation of angiotensin II. This inhibition will produce a secondary effect marked by the reduction of the expression of aldosterone synthase, TGF-B1 and thromboxane A2 and a reduction on the aldosterone receptor binding. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Torasemide is the diuretic with the highest oral bioavailability even in advanced stages of chronic kidney disease. This bioavailability tends to be higher than 80% regardless of the patient condition. The maximal serum concentration is reported to be of 1 hour and the absorption parameters are not affected by its use concomitantly with food. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of torasemide is 0.2 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Torasemide is found to be highly bound to plasma proteins, representing over 99% of the administered dose. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Torasemide is extensively metabolized in the liver and only 20% of the dose remains unchanged and it is recovered in the urine. Metabolized via the hepatic CYP2C8 and CYP2C9 mainly by reactions of hydroxylation, oxidation and reduction to 5 metabolites. The major metabolite, M5, is pharmacologically inactive. There are 2 minor metabolites, M1, possessing one-tenth the activity of torasemide, and M3, equal in activity to torasemide. Overall, torasemide appears to account for 80% of the total diuretic activity, while metabolites M1 and M3 account for 9% and 11%, respectively. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Torasemide is mainly hepatically processed and excreted in the feces from which about 70-80% of the administered dose is excreted by this pathway. On the other hand, about 20-30% of the administered dose is found in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The average half-life of torasemide is 3.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance rate of torasemide is considerably reduced by the presence of renal disorders. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD50 of torasemide in the rat is 5 g/kg. When overdose occurs, there is a marked diuresis with the danger of loss of fluid and electrolytes which has been seen to lead to somnolence, confusion, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, hemoconcentration dehydration and circulatory collapse. This effects can include some gastrointestinal disturbances. There is no increase in tumor incidence with torasemide and it is proven to not be mutagenic, not fetotoxic or teratogenic. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Demadex, Soaanz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Torasemida Torasemide Torasémide Torasemidum Torsemide •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Torasemide is a diuretic used to treat hypertension and edema associated with heart failure, renal failure, or liver disease. Output: The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. The severity of the interaction is moderate.

Does Bupropion and Trabectedin interact?

•Drug A: Bupropion •Drug B: Trabectedin •Severity: MAJOR •Description: The metabolism of Trabectedin can be decreased when combined with Bupropion. •Extended Description: The subject drug is known to be a strong inhibitor of CYP2D6 while the affected drug is reported to be metabolized by CYP2D6. Co-administration of these agents can produce an increase in the serum concentration of the affected drug as a result of a strong inhibition of CYP2D6 activity. This interaction may be significant as the affected drug has a narrow therapeutic index, therefore any increase in the serum concentration of this drug may lead to drastic effects on the tolerability of the medication and a significant increase in incidence or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated for treatment of advanced soft tissue sarcoma in patients refractory to or unsuitable to receive anthracycline or ifosfamide chemotherapy in Europe, Russia and South Korea. Approved for orphan drug status by the U.S. FDA for treatment of soft tissue sarcomas and ovarian cancer. Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, ovarian cancer, pediatric indications, sarcoma, and solid tumors. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Two of the rings in the drug's structure allows it to covalently bind to the minor groove of DNA. The third ring protrudes from the DNA which lets it interact with nearby nuclear proteins. This has the additive effect of blocking cell division at the G2 phase. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G2 phase, while cells at the G1 phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Administered intravenously. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 94 to 98% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 33-50 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Yondelis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trabectedin is an alkylating agent approved for the treatment of unresectable or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma).

The subject drug is known to be a strong inhibitor of CYP2D6 while the affected drug is reported to be metabolized by CYP2D6. Co-administration of these agents can produce an increase in the serum concentration of the affected drug as a result of a strong inhibition of CYP2D6 activity. This interaction may be significant as the affected drug has a narrow therapeutic index, therefore any increase in the serum concentration of this drug may lead to drastic effects on the tolerability of the medication and a significant increase in incidence or severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Trabectedin interact? Information: •Drug A: Bupropion •Drug B: Trabectedin •Severity: MAJOR •Description: The metabolism of Trabectedin can be decreased when combined with Bupropion. •Extended Description: The subject drug is known to be a strong inhibitor of CYP2D6 while the affected drug is reported to be metabolized by CYP2D6. Co-administration of these agents can produce an increase in the serum concentration of the affected drug as a result of a strong inhibition of CYP2D6 activity. This interaction may be significant as the affected drug has a narrow therapeutic index, therefore any increase in the serum concentration of this drug may lead to drastic effects on the tolerability of the medication and a significant increase in incidence or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated for treatment of advanced soft tissue sarcoma in patients refractory to or unsuitable to receive anthracycline or ifosfamide chemotherapy in Europe, Russia and South Korea. Approved for orphan drug status by the U.S. FDA for treatment of soft tissue sarcomas and ovarian cancer. Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, ovarian cancer, pediatric indications, sarcoma, and solid tumors. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Two of the rings in the drug's structure allows it to covalently bind to the minor groove of DNA. The third ring protrudes from the DNA which lets it interact with nearby nuclear proteins. This has the additive effect of blocking cell division at the G2 phase. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G2 phase, while cells at the G1 phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Administered intravenously. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 94 to 98% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 33-50 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Yondelis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trabectedin is an alkylating agent approved for the treatment of unresectable or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma). Output: The subject drug is known to be a strong inhibitor of CYP2D6 while the affected drug is reported to be metabolized by CYP2D6. Co-administration of these agents can produce an increase in the serum concentration of the affected drug as a result of a strong inhibition of CYP2D6 activity. This interaction may be significant as the affected drug has a narrow therapeutic index, therefore any increase in the serum concentration of this drug may lead to drastic effects on the tolerability of the medication and a significant increase in incidence or severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Tramadol interact?

•Drug A: Bupropion •Drug B: Tramadol •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Tramadol. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tramadol is approved for the management of moderate to severe pain in adults. Tramadol is also used off-label in the treatment of premature ejaculation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tramadol modulates the descending pain pathways within the central nervous system through the binding of parent and M1 metabolite to μ-opioid receptors and the weak inhibition of the reuptake of norepinephrine and serotonin. Apart from analgesia, tramadol may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. Central Nervous System In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Tramadol produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO2 tension and to electrical stimulation. Tramadol depresses the cough reflex by a direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose. Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections), or with concomitant use of other drugs known to reduce the seizure threshold. Tramadol can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g., anti-depressants, migraine medications). Treatment with the serotoninergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Tramadol should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, St. John’s Wort) due to the risk of serotonin syndrome. Gastrointestinal Tract and Other Smooth Muscle Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase. Endocrine System Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes. Hyponatremia has been reported very rarely with the use of tramadol, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diuretics). In some reports, hyponatremia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of tramadol and appropriate treatment (e.g., fluid restriction). During tramadol treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors. Cardiovascular Tramadol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquillizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of tramadol. QTc-Interval Prolongation The maximum placebo-adjusted mean change from baseline in the QTcF interval was 5.5 ms in the 400 mg/day treatment arm and 6.5 ms in the 600 mg/day mg treatment arm, both occurring at the 8h time point. Both treatment groups were within the 10 ms threshold for QT prolongation. Post-marketing experience with the use of tramadol containing products included rare reports of QT prolongation reported with an overdose. Particular care should be exercised when administering tramadol to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug. Abuse and Misuse Like all opioids, tramadol has the potential for abuse and misuse, which can lead to overdose and death. Therefore, tramadol should be prescribed and handled with caution. Dependence/Tolerance Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tramadol is a centrally acting μ-opioid receptor agonist and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine. Tramadol binds weakly to κ- and δ-opioid receptors and to the μ-opioid receptor with 6000-fold less affinity than morphine. Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol has also been shown to affect a number of pain modulators including alpha2-adrenoreceptors, neurokinin 1 receptors, the voltage-gated sodium channel type II alpha subunit, transient receptor potential cation channel subfamily V member 1 (TRPV1 - also known as the capsaicin receptor), muscarinic receptors (M1 and M3), N-methyl-D-aspartate receptor (also known as the NMDA receptor or glutamate receptor), Adenosine A1 receptors, and nicotinic acetylcholine receptor. In addition to the above neuronal targets, tramadol has a number of effects on inflammatory and immune mediators involved in the pain response. This includes inhibitory effects on cytokines, prostaglandin E2 (PGE2), nuclear factor-κB, and glial cells as well as a change in the polarization state of M1 macrophages. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Oral Administration Tramadol is administered as a racemate, with both the [-] and [+] forms of both tramadol and the M1 metabolite detected in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively. Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction. Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability. Intramuscular Administration Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166μg/L was found with a Tmax of 0.75 hours. Rectal Administration Following rectal administration with suppositories containing 100mg of tramadol, Cmax of 294μg/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration. Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): About 20% of the administered dose is found to bind to plasma proteins. Protein binding appears to be independent of concentrations up to 10μg/mL. Saturation only occurs at concentrations outside of the clinical range. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tramadol undergoes extensive first-pass metabolism in the liver by N- and O- demethylation and conjugation. From the extensive metabolism, there have been identified at least 23 metabolites. There are two main metabolic pathways: the O-demethylation of tramadol to produce O-desmethyl-tramadol (M1) catalyzed by CYP2D6 and the N-demethylation to N-desmethyl-tramadol (M2) catalyzed by CYP3A4 and CYP2B6. The wide variability in the pharmacokinetic properties between patients can partly be ascribed to polymorphisms within the gene for CYP2D6 that determine its enzymatic activity. CYP2D6*1 is considered the wild-type allele associated with normal enzyme activity and the "extensive metabolizer" phenotype; 90-95% of Caucasians are considered "extensive metabolizers" (with normal CYP2D6 function) while the remaining 5-10% are considered "poor metabolizers" with reduced or non-functioning enzyme. CYP2D6 alleles associated with non-functioning enzyme include *3, *4, *5, and *6 while alleles associated with reduced activity include *9, *10, *17, and *41. Poor metabolizers have reduced activity of the CYP2D6 enzyme and therefore less production of tramadol metabolites M1 and M2, which ultimately results in a reduced analgesic effect as tramadol interacts with the μ-opioid receptor primarily via M1. There are also large differences in the frequency of these alleles between different ethnicities: *3, *4, *5, *6, and *41 are more common among Caucasians while *17 is more common in Africans for example. Compared to 5-10% of Caucasians, only ~1% of Asians are considered poor metabolizers, however Asian populations carry a much higher frequency (51%) of the CYP2D6*10 allele, which is relatively rare in Caucasian populations and results in higher exposure to tramadol. Some individuals are considered "ultra-rapid metabolizers", such as those carrying CYP2D6 gene duplications (CYP2D6*DUP) or multiplications. These individuals are at risk of intoxication or exaggerated effects of tramadol due to higher concentrations of its active metabolite (M1). The occurrence of this phenotype is seen in approximately 1% to 2% of East Asians (Chinese, Japanese, Korean), 1% to 10% of Caucasians, 3% to 4% of African-Americans, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). The FDA label recommends avoiding the use of tramadol in these individuals. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing. •Half-life (Drug A): 24 hours •Half-life (Drug B): Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The reported LD50 for tramadol, when administered orally in mice, is 350 mg/kg. In carcinogenic studies, there are reports of murine tumors which cannot be concluded to be carcinogenic in humans. On the other hand, tramadol showed no evidence to be mutagenic in different assays and does not have effects on fertility. However, there are clear reports of embryotoxicity and fetotoxicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Conzip, Durela, Qdolo, Ralivia, Ryzolt, Seglentis, Tridural, Ultracet, Ultram, Zytram •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tramadol is a centrally-acting opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) used for the management of moderate to severe pain in adults.

Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Question: Does Bupropion and Tramadol interact? Information: •Drug A: Bupropion •Drug B: Tramadol •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Tramadol. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tramadol is approved for the management of moderate to severe pain in adults. Tramadol is also used off-label in the treatment of premature ejaculation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tramadol modulates the descending pain pathways within the central nervous system through the binding of parent and M1 metabolite to μ-opioid receptors and the weak inhibition of the reuptake of norepinephrine and serotonin. Apart from analgesia, tramadol may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. Central Nervous System In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Tramadol produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO2 tension and to electrical stimulation. Tramadol depresses the cough reflex by a direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose. Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections), or with concomitant use of other drugs known to reduce the seizure threshold. Tramadol can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g., anti-depressants, migraine medications). Treatment with the serotoninergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Tramadol should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, St. John’s Wort) due to the risk of serotonin syndrome. Gastrointestinal Tract and Other Smooth Muscle Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase. Endocrine System Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes. Hyponatremia has been reported very rarely with the use of tramadol, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diuretics). In some reports, hyponatremia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of tramadol and appropriate treatment (e.g., fluid restriction). During tramadol treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors. Cardiovascular Tramadol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquillizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of tramadol. QTc-Interval Prolongation The maximum placebo-adjusted mean change from baseline in the QTcF interval was 5.5 ms in the 400 mg/day treatment arm and 6.5 ms in the 600 mg/day mg treatment arm, both occurring at the 8h time point. Both treatment groups were within the 10 ms threshold for QT prolongation. Post-marketing experience with the use of tramadol containing products included rare reports of QT prolongation reported with an overdose. Particular care should be exercised when administering tramadol to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug. Abuse and Misuse Like all opioids, tramadol has the potential for abuse and misuse, which can lead to overdose and death. Therefore, tramadol should be prescribed and handled with caution. Dependence/Tolerance Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tramadol is a centrally acting μ-opioid receptor agonist and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine. Tramadol binds weakly to κ- and δ-opioid receptors and to the μ-opioid receptor with 6000-fold less affinity than morphine. Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol has also been shown to affect a number of pain modulators including alpha2-adrenoreceptors, neurokinin 1 receptors, the voltage-gated sodium channel type II alpha subunit, transient receptor potential cation channel subfamily V member 1 (TRPV1 - also known as the capsaicin receptor), muscarinic receptors (M1 and M3), N-methyl-D-aspartate receptor (also known as the NMDA receptor or glutamate receptor), Adenosine A1 receptors, and nicotinic acetylcholine receptor. In addition to the above neuronal targets, tramadol has a number of effects on inflammatory and immune mediators involved in the pain response. This includes inhibitory effects on cytokines, prostaglandin E2 (PGE2), nuclear factor-κB, and glial cells as well as a change in the polarization state of M1 macrophages. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Oral Administration Tramadol is administered as a racemate, with both the [-] and [+] forms of both tramadol and the M1 metabolite detected in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively. Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction. Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability. Intramuscular Administration Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166μg/L was found with a Tmax of 0.75 hours. Rectal Administration Following rectal administration with suppositories containing 100mg of tramadol, Cmax of 294μg/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration. Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): About 20% of the administered dose is found to bind to plasma proteins. Protein binding appears to be independent of concentrations up to 10μg/mL. Saturation only occurs at concentrations outside of the clinical range. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Tramadol undergoes extensive first-pass metabolism in the liver by N- and O- demethylation and conjugation. From the extensive metabolism, there have been identified at least 23 metabolites. There are two main metabolic pathways: the O-demethylation of tramadol to produce O-desmethyl-tramadol (M1) catalyzed by CYP2D6 and the N-demethylation to N-desmethyl-tramadol (M2) catalyzed by CYP3A4 and CYP2B6. The wide variability in the pharmacokinetic properties between patients can partly be ascribed to polymorphisms within the gene for CYP2D6 that determine its enzymatic activity. CYP2D6*1 is considered the wild-type allele associated with normal enzyme activity and the "extensive metabolizer" phenotype; 90-95% of Caucasians are considered "extensive metabolizers" (with normal CYP2D6 function) while the remaining 5-10% are considered "poor metabolizers" with reduced or non-functioning enzyme. CYP2D6 alleles associated with non-functioning enzyme include *3, *4, *5, and *6 while alleles associated with reduced activity include *9, *10, *17, and *41. Poor metabolizers have reduced activity of the CYP2D6 enzyme and therefore less production of tramadol metabolites M1 and M2, which ultimately results in a reduced analgesic effect as tramadol interacts with the μ-opioid receptor primarily via M1. There are also large differences in the frequency of these alleles between different ethnicities: *3, *4, *5, *6, and *41 are more common among Caucasians while *17 is more common in Africans for example. Compared to 5-10% of Caucasians, only ~1% of Asians are considered poor metabolizers, however Asian populations carry a much higher frequency (51%) of the CYP2D6*10 allele, which is relatively rare in Caucasian populations and results in higher exposure to tramadol. Some individuals are considered "ultra-rapid metabolizers", such as those carrying CYP2D6 gene duplications (CYP2D6*DUP) or multiplications. These individuals are at risk of intoxication or exaggerated effects of tramadol due to higher concentrations of its active metabolite (M1). The occurrence of this phenotype is seen in approximately 1% to 2% of East Asians (Chinese, Japanese, Korean), 1% to 10% of Caucasians, 3% to 4% of African-Americans, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). The FDA label recommends avoiding the use of tramadol in these individuals. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing. •Half-life (Drug A): 24 hours •Half-life (Drug B): Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The reported LD50 for tramadol, when administered orally in mice, is 350 mg/kg. In carcinogenic studies, there are reports of murine tumors which cannot be concluded to be carcinogenic in humans. On the other hand, tramadol showed no evidence to be mutagenic in different assays and does not have effects on fertility. However, there are clear reports of embryotoxicity and fetotoxicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Conzip, Durela, Qdolo, Ralivia, Ryzolt, Seglentis, Tridural, Ultracet, Ultram, Zytram •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tramadol is a centrally-acting opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) used for the management of moderate to severe pain in adults. Output: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Does Bupropion and Trametinib interact?

•Drug A: Bupropion •Drug B: Trametinib •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Trametinib which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Trametinib is indicated as monotherapy for the treatment of BRAF-inhibitor treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. It is used in combination with dabrafenib for the: treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations. adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection. treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation. In Europe, it is indicated for the treatment of adults with advanced non-small cell lung cancer with a BRAF V600 mutation. treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options. the treatment of adult and pediatric patients six years of age and older with unresectable or metastatic solid tumours with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. In the US, this indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). the treatment of pediatric patients one year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. In the US, BRAF V600E or V600K mutations must be detected by an FDA-approved test. Trametinib is not indicated for the treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumours in vitro and in vivo. Trametinib is often used in combination with dabrafenib, a BRAF inhibitor. In BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) pathway, also known as the RAS-RAF-MEK-ERK pathway, activates a cascade of cell surface receptors and intracellular downstream signalling molecules. Activated RAS protein activates RAF, a serine/threonine kinase that activates other downstream proteins such as mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2. MEKs then activates ERK, which works on several target proteins and nuclear transcription factors that regulate cell proliferation, differentiation, survival, and growth. ARAF, BRAF, and CRAF are three isoforms of RAF identified in humans. In particular, BRAF is known to be the most critical activator in melanoma. Certain cancers, such as melanoma, are associated with BRAF mutations, with one study suggesting that BRAF is mutated in about 50% of melanoma tumours. BRAF V600E and V600K mutations account for 95% of BRAF mutations. These BRAF mutations cause constitutive activation of the RAS-RAF-MEK-ERK pathway, leading to dysregulated proliferation and survival of tumour cells. Trametinib is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2. By binding to unphosphorylated MEK1 and MEK2 with high affinity, trametinib blocks the catalytic activity of MEKs. It also maintains MEK in an unphosphorylated form, preventing phosphorylation and activation of MEKs. In vitro studies suggest that dual inhibition of the MAPK pathway by MEK and B-RAF inhibitors is associated with a synergistic effect and improved therapeutic efficacy in cancers compared to using either drug alone. The combined use of trametinib and dabrafenib, a BRAF inhibitor, results in more significant growth inhibition of BRAF V600 mutation-positive tumour cell lines in vitro and prolonged inhibition of tumour growth in BRAF V600 mutation-positive tumour xenografts compared to either drug alone. The combined inhibition of MEK by trametinib and RAF by dabrafenib delays the emergence of resistance in vivo in BRAF V600 mutation-positive melanoma xenografts. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Following oral administration, trametinib is rapidly and readily absorbed. The absorption was examined in patients with solid tumours and BRAF V600 mutation-positive metastatic melanoma. Following the administration of trametinib tablets 0.125 mg (0.0625 times the approved recommended adult dosage) to 4 mg (2 times the approved recommended adult dosage) daily, both C max and AUC increased dose-proportionally. Intersubject variability in AUC and C max at steady state is 22% and 28%, respectively. Trametinib accumulates with daily repeat dosing with a mean accumulation ratio of 6.0 at 2 mg once daily dose. Steady-state was achieved by Day 15. The mean absolute bioavailability of trametinib is 72% for oral tablets and 81% for oral solution. The T max is 1.5 hours. A high-fat, high-calorie meal (approximately 1000 calories) decreased trametinib AUC by 24% and C max by 70%, and delayed T max by approximately four hours as compared with fasted conditions. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution (V c /F) is 214 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Trametinib is 97.4% bound to human plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Trametinib predominantly undergoes deacetylation mediated by carboxylesterases (i.e., carboxylesterase 1b/c and 2) and other hydrolytic enzymes. The deacetylated metabolite may further be glucuronidated. In vitro findings suggest that deacetylation may also be accompanied by mono-oxygenation, hydroxylation, and glucuronidation. CYP3A4-mediated oxidation is a minor pathway. Four metabolites (M1/2/3/4) have been characterized in patients with advanced cancers. In vitro, the M1 and M3 metabolites demonstrated approximately equal or 10-fold less potent phospho-MEK1-inhibiting activity than the parent compound. Following a single dose of [ C]-trametinib, approximately 50% of circulating radioactivity represented the parent compound. According to findings from metabolite profiling after repeat dosing of trametinib, unchanged parent drug accounted for greater than or equal to 75% of drug-related material in plasma. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following oral administration of [ C]-trametinib, greater than 80% of excreted radioactivity was recovered in the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the excreted dose as the parent molecule. •Half-life (Drug A): 24 hours •Half-life (Drug B): The estimated elimination half-life is 3.9 to 4.8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance is 4.9 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): There is no information regarding the acute toxicity (LD 50 ) of trametinib. The highest doses of trametinib evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on two consecutive days, followed by 3 mg once daily. Out of seven patients treated on one of these two schedules, two patients experienced retinal pigment epithelial detachments. In clinical trials with trametinib monotherapy, one case of accidental overdose was reported from a single dose of 4 mg: no adverse events were reported in this event. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of drug overdose. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Mekinist •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trametinib is a kinase inhibitor used alone or in combination with dabrafenib to treat patients with cancers with specific BRAF mutations, such as melanoma and non-small cell lung cancer.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Trametinib interact? Information: •Drug A: Bupropion •Drug B: Trametinib •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Trametinib which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Trametinib is indicated as monotherapy for the treatment of BRAF-inhibitor treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. It is used in combination with dabrafenib for the: treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations. adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection. treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation. In Europe, it is indicated for the treatment of adults with advanced non-small cell lung cancer with a BRAF V600 mutation. treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options. the treatment of adult and pediatric patients six years of age and older with unresectable or metastatic solid tumours with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. In the US, this indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). the treatment of pediatric patients one year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. In the US, BRAF V600E or V600K mutations must be detected by an FDA-approved test. Trametinib is not indicated for the treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumours in vitro and in vivo. Trametinib is often used in combination with dabrafenib, a BRAF inhibitor. In BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) pathway, also known as the RAS-RAF-MEK-ERK pathway, activates a cascade of cell surface receptors and intracellular downstream signalling molecules. Activated RAS protein activates RAF, a serine/threonine kinase that activates other downstream proteins such as mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2. MEKs then activates ERK, which works on several target proteins and nuclear transcription factors that regulate cell proliferation, differentiation, survival, and growth. ARAF, BRAF, and CRAF are three isoforms of RAF identified in humans. In particular, BRAF is known to be the most critical activator in melanoma. Certain cancers, such as melanoma, are associated with BRAF mutations, with one study suggesting that BRAF is mutated in about 50% of melanoma tumours. BRAF V600E and V600K mutations account for 95% of BRAF mutations. These BRAF mutations cause constitutive activation of the RAS-RAF-MEK-ERK pathway, leading to dysregulated proliferation and survival of tumour cells. Trametinib is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2. By binding to unphosphorylated MEK1 and MEK2 with high affinity, trametinib blocks the catalytic activity of MEKs. It also maintains MEK in an unphosphorylated form, preventing phosphorylation and activation of MEKs. In vitro studies suggest that dual inhibition of the MAPK pathway by MEK and B-RAF inhibitors is associated with a synergistic effect and improved therapeutic efficacy in cancers compared to using either drug alone. The combined use of trametinib and dabrafenib, a BRAF inhibitor, results in more significant growth inhibition of BRAF V600 mutation-positive tumour cell lines in vitro and prolonged inhibition of tumour growth in BRAF V600 mutation-positive tumour xenografts compared to either drug alone. The combined inhibition of MEK by trametinib and RAF by dabrafenib delays the emergence of resistance in vivo in BRAF V600 mutation-positive melanoma xenografts. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Following oral administration, trametinib is rapidly and readily absorbed. The absorption was examined in patients with solid tumours and BRAF V600 mutation-positive metastatic melanoma. Following the administration of trametinib tablets 0.125 mg (0.0625 times the approved recommended adult dosage) to 4 mg (2 times the approved recommended adult dosage) daily, both C max and AUC increased dose-proportionally. Intersubject variability in AUC and C max at steady state is 22% and 28%, respectively. Trametinib accumulates with daily repeat dosing with a mean accumulation ratio of 6.0 at 2 mg once daily dose. Steady-state was achieved by Day 15. The mean absolute bioavailability of trametinib is 72% for oral tablets and 81% for oral solution. The T max is 1.5 hours. A high-fat, high-calorie meal (approximately 1000 calories) decreased trametinib AUC by 24% and C max by 70%, and delayed T max by approximately four hours as compared with fasted conditions. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution (V c /F) is 214 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Trametinib is 97.4% bound to human plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Trametinib predominantly undergoes deacetylation mediated by carboxylesterases (i.e., carboxylesterase 1b/c and 2) and other hydrolytic enzymes. The deacetylated metabolite may further be glucuronidated. In vitro findings suggest that deacetylation may also be accompanied by mono-oxygenation, hydroxylation, and glucuronidation. CYP3A4-mediated oxidation is a minor pathway. Four metabolites (M1/2/3/4) have been characterized in patients with advanced cancers. In vitro, the M1 and M3 metabolites demonstrated approximately equal or 10-fold less potent phospho-MEK1-inhibiting activity than the parent compound. Following a single dose of [ C]-trametinib, approximately 50% of circulating radioactivity represented the parent compound. According to findings from metabolite profiling after repeat dosing of trametinib, unchanged parent drug accounted for greater than or equal to 75% of drug-related material in plasma. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following oral administration of [ C]-trametinib, greater than 80% of excreted radioactivity was recovered in the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the excreted dose as the parent molecule. •Half-life (Drug A): 24 hours •Half-life (Drug B): The estimated elimination half-life is 3.9 to 4.8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance is 4.9 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): There is no information regarding the acute toxicity (LD 50 ) of trametinib. The highest doses of trametinib evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on two consecutive days, followed by 3 mg once daily. Out of seven patients treated on one of these two schedules, two patients experienced retinal pigment epithelial detachments. In clinical trials with trametinib monotherapy, one case of accidental overdose was reported from a single dose of 4 mg: no adverse events were reported in this event. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of drug overdose. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Mekinist •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trametinib is a kinase inhibitor used alone or in combination with dabrafenib to treat patients with cancers with specific BRAF mutations, such as melanoma and non-small cell lung cancer. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Tranylcypromine interact?

•Drug A: Bupropion •Drug B: Tranylcypromine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Tranylcypromine is combined with Bupropion. •Extended Description: Bupropion is a dopaminergic agent that is used in the treatment of Parkinson's disease, depression, and smoking cessation. Based on the findings from animal studies, co-administration of bupropion with monoamine oxidase inhibitors may enhance the acute toxicity effects of bupropion, as indicated by an increase in mortality and a decrease in time to death . This interaction applies to both immediate release and sustained release forms of bupropion. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of major depressive episode without melancholia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tranylcypromine belongs to a class of antidepressants called monoamine oxidase inhibitors (MAOIs). Tranylcypromine is a non-hydrazine monoamine oxidase inhibitor with a rapid onset of activity. MAO is an enzyme that catalyzes the oxidative deamination of a number of amines, including serotonin, norepinephrine, epinephrine, and dopamine. Two isoforms of MAO, A and B, are found in the body. MAO-A is mainly found within cells located in the periphery and catalyzes the breakdown of serotonin, norepinephrine, epinephrine, dopamine and tyramine. MAO-B acts on phenylethylamine, norepinephrine, epinephrine, dopamine and tyramine, is localized extracellularly and is found predominantly in the brain. While the mechanism of MAOIs is still unclear, it is thought that they act by increasing free serotonin and norepinephrine concentrations and/or by altering the concentrations of other amines in the CNS. It has been postulated that depression is caused by low levels of serotonin and/or norepinephrine and that increasing serotonergic and norepinephrinergic neurotransmission results in relief of depressive symptoms. MAO A inhibition is thought to be more relevant to antidepressant activity than MAO B inhibition. Selective MAO B inhibitors, such as selegiline, have no antidepressant effects. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tranylcypromine irreversibly and nonselectively inhibits monoamine oxidase (MAO). Within neurons, MAO appears to regulate the levels of monoamines released upon synaptic firing. Since depression is associated with low levels of monoamines, the inhibition of MAO serves to ease depressive symptoms, as this results in an increase in the concentrations of these amines within the CNS. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Interindividual variability in absorption. May be biphasic in some individuals. Peak plasma concentrations occur in one hour following oral administration with a secondary peak occurring within 2-3 hours. Biphasic absorption may represent different rates of absorption of the stereoisomers of the drug, though additional studies are required to confirm this. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 1.1-5.7 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 1.5-3.2 hours in patients with normal renal and hepatic function •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): In overdosage, some patients exhibit insomnia, restlessness and anxiety, progressing in severe cases to agitation, mental confusion and incoherence. Hypotension, dizziness, weakness and drowsiness may occur, progressing in severe cases to extreme dizziness and shock. A few patients have displayed hypertension with severe headache and other symptoms. Rare instances have been reported in which hypertension was accompanied by twitching or myoclonic fibrillation of skeletal muscles with hyperpyrexia, sometimes progressing to generalized rigidity and coma. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Parnate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): dl-tranylcypromine Racemic Tranylcypromine Tranilcipromina Transamine Tranylcypromin Tranylcypromine Tranylcyprominum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tranylcypromine is a monoamine oxidase inhibitor used to treat major depressive disorder.

Bupropion is a dopaminergic agent that is used in the treatment of Parkinson's disease, depression, and smoking cessation. Based on the findings from animal studies, co-administration of bupropion with monoamine oxidase inhibitors may enhance the acute toxicity effects of bupropion, as indicated by an increase in mortality and a decrease in time to death . This interaction applies to both immediate release and sustained release forms of bupropion. The severity of the interaction is major.

Question: Does Bupropion and Tranylcypromine interact? Information: •Drug A: Bupropion •Drug B: Tranylcypromine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Tranylcypromine is combined with Bupropion. •Extended Description: Bupropion is a dopaminergic agent that is used in the treatment of Parkinson's disease, depression, and smoking cessation. Based on the findings from animal studies, co-administration of bupropion with monoamine oxidase inhibitors may enhance the acute toxicity effects of bupropion, as indicated by an increase in mortality and a decrease in time to death . This interaction applies to both immediate release and sustained release forms of bupropion. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of major depressive episode without melancholia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tranylcypromine belongs to a class of antidepressants called monoamine oxidase inhibitors (MAOIs). Tranylcypromine is a non-hydrazine monoamine oxidase inhibitor with a rapid onset of activity. MAO is an enzyme that catalyzes the oxidative deamination of a number of amines, including serotonin, norepinephrine, epinephrine, and dopamine. Two isoforms of MAO, A and B, are found in the body. MAO-A is mainly found within cells located in the periphery and catalyzes the breakdown of serotonin, norepinephrine, epinephrine, dopamine and tyramine. MAO-B acts on phenylethylamine, norepinephrine, epinephrine, dopamine and tyramine, is localized extracellularly and is found predominantly in the brain. While the mechanism of MAOIs is still unclear, it is thought that they act by increasing free serotonin and norepinephrine concentrations and/or by altering the concentrations of other amines in the CNS. It has been postulated that depression is caused by low levels of serotonin and/or norepinephrine and that increasing serotonergic and norepinephrinergic neurotransmission results in relief of depressive symptoms. MAO A inhibition is thought to be more relevant to antidepressant activity than MAO B inhibition. Selective MAO B inhibitors, such as selegiline, have no antidepressant effects. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tranylcypromine irreversibly and nonselectively inhibits monoamine oxidase (MAO). Within neurons, MAO appears to regulate the levels of monoamines released upon synaptic firing. Since depression is associated with low levels of monoamines, the inhibition of MAO serves to ease depressive symptoms, as this results in an increase in the concentrations of these amines within the CNS. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Interindividual variability in absorption. May be biphasic in some individuals. Peak plasma concentrations occur in one hour following oral administration with a secondary peak occurring within 2-3 hours. Biphasic absorption may represent different rates of absorption of the stereoisomers of the drug, though additional studies are required to confirm this. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 1.1-5.7 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 1.5-3.2 hours in patients with normal renal and hepatic function •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): In overdosage, some patients exhibit insomnia, restlessness and anxiety, progressing in severe cases to agitation, mental confusion and incoherence. Hypotension, dizziness, weakness and drowsiness may occur, progressing in severe cases to extreme dizziness and shock. A few patients have displayed hypertension with severe headache and other symptoms. Rare instances have been reported in which hypertension was accompanied by twitching or myoclonic fibrillation of skeletal muscles with hyperpyrexia, sometimes progressing to generalized rigidity and coma. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Parnate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): dl-tranylcypromine Racemic Tranylcypromine Tranilcipromina Transamine Tranylcypromin Tranylcypromine Tranylcyprominum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tranylcypromine is a monoamine oxidase inhibitor used to treat major depressive disorder. Output: Bupropion is a dopaminergic agent that is used in the treatment of Parkinson's disease, depression, and smoking cessation. Based on the findings from animal studies, co-administration of bupropion with monoamine oxidase inhibitors may enhance the acute toxicity effects of bupropion, as indicated by an increase in mortality and a decrease in time to death . This interaction applies to both immediate release and sustained release forms of bupropion. The severity of the interaction is major.

Does Bupropion and Trazodone interact?

•Drug A: Bupropion •Drug B: Trazodone •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Trazodone. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Trazodone is indicated for the treatment of major depressive disorder (MDD). It has been used off-label for adjunct therapy in alcohol dependence, and off-label to treat anxiety and insomnia. It may also be used off-label to treat symptoms of dementia, Alzheimer’s disease, schizophrenia, eating disorders, and fibromyalgia due to its effects on various neurotransmitter receptors. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. It is known to prolong the cardiac QT-interval. Memory, alertness, and cognition may be decreased by trazodone, especially in elderly patients due to its central nervous system depressant effects. A note on priapism Trazodone has been associated with the occurrence of priapism, a painful and persistent incidence of penile tissue erection that is unrelievable and can cause permanent neurological damage if left untreated. Patients must be advised to seek immediate medical attention if priapism is suspected. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The plasma protein binding of trazodone is 89-95% according to in vitro studies. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Less than 1% of an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine as unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD50 of trazodone is 690 mg/kg in rats. An overdose of trazodone may result in central nervous system, cardiac, respiratory effects. Signs and symptoms may include dyspnea, bradycardia, hypotension, mental status changes, lack of coordination, and coma, among others. In addition, an overdose may result in priapism, a persistent unrelievable penile tissue erection that may cause permanent damage if not treated promptly. No specific antidote exists for a trazodone overdose. If an overdose occurs, consider the possibility that trazodone may have been combined with other drugs. Contact a poison control center in case of overdose for the most current management guidelines. Dialysis does not accelerate trazodone clearance. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Desyrel, Oleptro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trazodona Trazodone Trazodonum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trazodone is a serotonin uptake inhibitor used to treat major depressive disorder.

Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Question: Does Bupropion and Trazodone interact? Information: •Drug A: Bupropion •Drug B: Trazodone •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Trazodone. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Trazodone is indicated for the treatment of major depressive disorder (MDD). It has been used off-label for adjunct therapy in alcohol dependence, and off-label to treat anxiety and insomnia. It may also be used off-label to treat symptoms of dementia, Alzheimer’s disease, schizophrenia, eating disorders, and fibromyalgia due to its effects on various neurotransmitter receptors. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. It is known to prolong the cardiac QT-interval. Memory, alertness, and cognition may be decreased by trazodone, especially in elderly patients due to its central nervous system depressant effects. A note on priapism Trazodone has been associated with the occurrence of priapism, a painful and persistent incidence of penile tissue erection that is unrelievable and can cause permanent neurological damage if left untreated. Patients must be advised to seek immediate medical attention if priapism is suspected. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The plasma protein binding of trazodone is 89-95% according to in vitro studies. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Less than 1% of an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine as unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD50 of trazodone is 690 mg/kg in rats. An overdose of trazodone may result in central nervous system, cardiac, respiratory effects. Signs and symptoms may include dyspnea, bradycardia, hypotension, mental status changes, lack of coordination, and coma, among others. In addition, an overdose may result in priapism, a persistent unrelievable penile tissue erection that may cause permanent damage if not treated promptly. No specific antidote exists for a trazodone overdose. If an overdose occurs, consider the possibility that trazodone may have been combined with other drugs. Contact a poison control center in case of overdose for the most current management guidelines. Dialysis does not accelerate trazodone clearance. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Desyrel, Oleptro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trazodona Trazodone Trazodonum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trazodone is a serotonin uptake inhibitor used to treat major depressive disorder. Output: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Does Bupropion and Treprostinil interact?

•Drug A: Bupropion •Drug B: Treprostinil •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Treprostinil. •Extended Description: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): The FDA has indicated treprostinil for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease to improve exercise ability. It is also used to treat pulmonary arterial hypertension in patients requiring transition from epoprostenol. The Health Canada label specifies that treprostinil is indicated for the long-term treatment of pulmonary arterial hypertension in NYHA Class III and IV patients who did not respond adequately to conventional therapy. L24244 •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): As an analogue of prostacyclin, treprostinil promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In animals, the vasodilatory effects of treprostinil lead to a reduction of right and left ventricular afterload and an increase in cardiac output and stroke volume. Treprostinil also causes a dose-related negative inotropic and lusitropic effect, and no major effects on cardiac conduction have been detected. Short-lasting effects on QTc were detected in healthy volunteers (n=240) given inhaled single doses of 54 and 84 μg of treprostinil. These effects dissipated rapidly as treprostinil concentrations lowered. When given subcutaneously or intravenously, treprostinil has the potential to reach higher concentrations. The effect of oral treprostinil on QTc has not been evaluated. Due to its ability to inhibit platelet aggregation, treprostinil can increase the risk of bleeding, and patients with low systemic arterial pressure taking treprostinil may experience symptomatic hypotension. The abrupt withdrawal of treprostinil or drastic changes in dose may worsen the symptoms of pulmonary arterial hypertension (PAH). The inhalation of treprostinil can also cause bronchospasms in patients with asthma, chronic obstructive pulmonary disease (COPD), or bronchial hyperreactivity. When given intravenously, treprostinil can lead to infusion complications and increase the risk of bloodstream infections. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Treprostinil is a stable analogue of prostacyclin, a prostaglandin that acts as an anti-thrombotic agent and a potent vasodilator. Prostacyclin analogues are useful in the treatment of pulmonary arterial hypertension (PAH), a disease characterized by abnormally high blood pressure in the arteries between the heart and lungs. PAH leads to right heart failure due to the remodelling of pulmonary arteries, and patients with this condition have a poor prognosis. Treprostinil binds and activates the prostacyclin receptor, the prostaglandin D2 receptor 1, and the prostaglandin E2 receptor 2. The activation of these receptors leads to the elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which consequently promotes the opening of calcium-activated potassium channels that lead to cell hyperpolarization. This mechanism promotes the direct vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In addition to its direct vasodilatory effects, treprostinil inhibits inflammatory pathways. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After subcutaneous infusion, treprostinil is completely absorbed, with a bioavailability of about 100%, and it reaches steady-state concentrations in approximately 10 hours. The pharmacokinetics of treprostinil follow a two-compartment model and are linear between 2.5 and 125 ng/kg/min. Subcutaneous and intravenous doses of treprostinil are bioequivalent at 10 ng/kg/min. Compared to healthy subjects, patients with mild and moderate hepatic insufficiency had a corresponding C max 2- and 4-times higher and an AUC 0-∞ 3- and 5-times higher when given a subcutaneous treprostinil dose of 10 ng/kg/min for 150 min. When given orally at doses between 0.5 and 15 mg twice a day, treprostinil follows a dose-proportional pharmacokinetic profile. The oral bioavailability of treprostinil is 17%, and drug concentration reaches its highest level between 4 and 6 hours after oral administration. The oral absorption of treprostinil is affected by food. The AUC and C max of oral treprostinil increase 49% and 13%, respectively, when this drug is administered with a high-fat, high-calorie meal. The AUC and C max of inhaled treprostinil were proportional to the doses administered (18 to 90 μg). The bioavailability of inhaled treprostinil was 64% in patients receiving 2 doses of 18 μg, and 72% in patients receiving two doses of 36 μg. Two separate studies that evaluated the pharmacokinetics of inhaled treprostinil at a maintenance dose of 54 μg found that the mean C max was 0.91 and 1.32 ng/mL, respectively, with a corresponding T max of 0.25 and 0.12 hr and a mean AUC of 0.81 and 0.97 hr⋅ng/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of treprostinil is 14 L/70 kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): At in vitro concentrations ranging from 330 to 10,000 μg/L, the human plasma protein binding of treprostinil is approximately 91%. This concentration is above what is considered to be clinically relevant. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Treprostinil is mostly metabolized by the liver, mainly by CYP2C8, and by CYP2C9 to a lesser extent. Treprostinil does not have a single major metabolite. The five metabolites detected in urine (HU1 through HU5) accounted for 13.8, 14.3, 15.5, 10.6 and 10.2% of the dose, respectively. One of the metabolites (HU5) is the glucuronide conjugate of treprostinil. HU1, HU2, HU3 and HU4 are formed through the oxidation of the 3-hydroxyloctyl side chain. None of the metabolites of treprostinil appear to be active. In vitro studies suggest that treprostinil does not inhibit or induce any major CYP enzymes. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Treprostinil metabolites are excreted through urine (79%) and feces (13%) over 10 days. Only a small proportion of treprostinil is excreted unchanged. When administered orally, 1.13% and 0.19% of unchanged treprostinil diolamine are found in urine and feces, respectively. When administered subcutaneously, intravenously or by inhalation, 4% of unchanged treprostinil is found in urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The terminal elimination half-life of treprostinil is approximately 4 hours, following a two-compartment model. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of treprostinil is 30 L/hr in a 70 kg person. In patients with mild to moderate hepatic insufficiency, clearance is reduced up to 80%. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Treprostinil overdose symptoms are an extension of its dose-limiting pharmacologic effects. These include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most overdose events were self-limiting and resolved by reducing or withholding treprostinil. In studies where treprostinil was infused using an external pump, several patients received an overdose due to an accidental bolus administration, errors in the programmed delivery rate and incorrect prescriptions. Only two cases of of substantial hemodynamic concern were detected among patients that received an excess of treprostinil. A pediatric patient that accidentally received 7.5 mg of treprostinil via a central venous catheter presented flushing, headache, nausea, vomiting, hypotension, and seizure-like activity with loss of consciousness for several minutes. A rat study that evaluated the carcinogenic effects of inhaled treprostinil, found no evidence of carcinogenicity in levels up to 35 times the clinical exposure obtained with a maintenance dose of 54 μg. The infusion of treprostinil sodium did not affect fertility or mating performance in rats given subcutaneous treprostinil. Treprostinil did not show mutagenic or clastogenic effects in in vitro or in vivo studies. There was no significant increase of tumors in rats given up to 10 mg/kg/day of oral treprostinil diolamine. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Orenitram, Remodulin, Tyvaso •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Treprostinil is a prostacyclin vasodilator for the treatment of pulmonary arterial hypertension to relieve exercise associated symptoms and to prevent clinical deterioration after stopping epoprostenol.

Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Treprostinil interact? Information: •Drug A: Bupropion •Drug B: Treprostinil •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Treprostinil. •Extended Description: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): The FDA has indicated treprostinil for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease to improve exercise ability. It is also used to treat pulmonary arterial hypertension in patients requiring transition from epoprostenol. The Health Canada label specifies that treprostinil is indicated for the long-term treatment of pulmonary arterial hypertension in NYHA Class III and IV patients who did not respond adequately to conventional therapy. L24244 •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): As an analogue of prostacyclin, treprostinil promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In animals, the vasodilatory effects of treprostinil lead to a reduction of right and left ventricular afterload and an increase in cardiac output and stroke volume. Treprostinil also causes a dose-related negative inotropic and lusitropic effect, and no major effects on cardiac conduction have been detected. Short-lasting effects on QTc were detected in healthy volunteers (n=240) given inhaled single doses of 54 and 84 μg of treprostinil. These effects dissipated rapidly as treprostinil concentrations lowered. When given subcutaneously or intravenously, treprostinil has the potential to reach higher concentrations. The effect of oral treprostinil on QTc has not been evaluated. Due to its ability to inhibit platelet aggregation, treprostinil can increase the risk of bleeding, and patients with low systemic arterial pressure taking treprostinil may experience symptomatic hypotension. The abrupt withdrawal of treprostinil or drastic changes in dose may worsen the symptoms of pulmonary arterial hypertension (PAH). The inhalation of treprostinil can also cause bronchospasms in patients with asthma, chronic obstructive pulmonary disease (COPD), or bronchial hyperreactivity. When given intravenously, treprostinil can lead to infusion complications and increase the risk of bloodstream infections. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Treprostinil is a stable analogue of prostacyclin, a prostaglandin that acts as an anti-thrombotic agent and a potent vasodilator. Prostacyclin analogues are useful in the treatment of pulmonary arterial hypertension (PAH), a disease characterized by abnormally high blood pressure in the arteries between the heart and lungs. PAH leads to right heart failure due to the remodelling of pulmonary arteries, and patients with this condition have a poor prognosis. Treprostinil binds and activates the prostacyclin receptor, the prostaglandin D2 receptor 1, and the prostaglandin E2 receptor 2. The activation of these receptors leads to the elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which consequently promotes the opening of calcium-activated potassium channels that lead to cell hyperpolarization. This mechanism promotes the direct vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In addition to its direct vasodilatory effects, treprostinil inhibits inflammatory pathways. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After subcutaneous infusion, treprostinil is completely absorbed, with a bioavailability of about 100%, and it reaches steady-state concentrations in approximately 10 hours. The pharmacokinetics of treprostinil follow a two-compartment model and are linear between 2.5 and 125 ng/kg/min. Subcutaneous and intravenous doses of treprostinil are bioequivalent at 10 ng/kg/min. Compared to healthy subjects, patients with mild and moderate hepatic insufficiency had a corresponding C max 2- and 4-times higher and an AUC 0-∞ 3- and 5-times higher when given a subcutaneous treprostinil dose of 10 ng/kg/min for 150 min. When given orally at doses between 0.5 and 15 mg twice a day, treprostinil follows a dose-proportional pharmacokinetic profile. The oral bioavailability of treprostinil is 17%, and drug concentration reaches its highest level between 4 and 6 hours after oral administration. The oral absorption of treprostinil is affected by food. The AUC and C max of oral treprostinil increase 49% and 13%, respectively, when this drug is administered with a high-fat, high-calorie meal. The AUC and C max of inhaled treprostinil were proportional to the doses administered (18 to 90 μg). The bioavailability of inhaled treprostinil was 64% in patients receiving 2 doses of 18 μg, and 72% in patients receiving two doses of 36 μg. Two separate studies that evaluated the pharmacokinetics of inhaled treprostinil at a maintenance dose of 54 μg found that the mean C max was 0.91 and 1.32 ng/mL, respectively, with a corresponding T max of 0.25 and 0.12 hr and a mean AUC of 0.81 and 0.97 hr⋅ng/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of treprostinil is 14 L/70 kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): At in vitro concentrations ranging from 330 to 10,000 μg/L, the human plasma protein binding of treprostinil is approximately 91%. This concentration is above what is considered to be clinically relevant. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Treprostinil is mostly metabolized by the liver, mainly by CYP2C8, and by CYP2C9 to a lesser extent. Treprostinil does not have a single major metabolite. The five metabolites detected in urine (HU1 through HU5) accounted for 13.8, 14.3, 15.5, 10.6 and 10.2% of the dose, respectively. One of the metabolites (HU5) is the glucuronide conjugate of treprostinil. HU1, HU2, HU3 and HU4 are formed through the oxidation of the 3-hydroxyloctyl side chain. None of the metabolites of treprostinil appear to be active. In vitro studies suggest that treprostinil does not inhibit or induce any major CYP enzymes. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Treprostinil metabolites are excreted through urine (79%) and feces (13%) over 10 days. Only a small proportion of treprostinil is excreted unchanged. When administered orally, 1.13% and 0.19% of unchanged treprostinil diolamine are found in urine and feces, respectively. When administered subcutaneously, intravenously or by inhalation, 4% of unchanged treprostinil is found in urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The terminal elimination half-life of treprostinil is approximately 4 hours, following a two-compartment model. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of treprostinil is 30 L/hr in a 70 kg person. In patients with mild to moderate hepatic insufficiency, clearance is reduced up to 80%. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Treprostinil overdose symptoms are an extension of its dose-limiting pharmacologic effects. These include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most overdose events were self-limiting and resolved by reducing or withholding treprostinil. In studies where treprostinil was infused using an external pump, several patients received an overdose due to an accidental bolus administration, errors in the programmed delivery rate and incorrect prescriptions. Only two cases of of substantial hemodynamic concern were detected among patients that received an excess of treprostinil. A pediatric patient that accidentally received 7.5 mg of treprostinil via a central venous catheter presented flushing, headache, nausea, vomiting, hypotension, and seizure-like activity with loss of consciousness for several minutes. A rat study that evaluated the carcinogenic effects of inhaled treprostinil, found no evidence of carcinogenicity in levels up to 35 times the clinical exposure obtained with a maintenance dose of 54 μg. The infusion of treprostinil sodium did not affect fertility or mating performance in rats given subcutaneous treprostinil. Treprostinil did not show mutagenic or clastogenic effects in in vitro or in vivo studies. There was no significant increase of tumors in rats given up to 10 mg/kg/day of oral treprostinil diolamine. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Orenitram, Remodulin, Tyvaso •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Treprostinil is a prostacyclin vasodilator for the treatment of pulmonary arterial hypertension to relieve exercise associated symptoms and to prevent clinical deterioration after stopping epoprostenol. Output: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. The severity of the interaction is minor.

Does Bupropion and Triamterene interact?

•Drug A: Bupropion •Drug B: Triamterene •Severity: MODERATE •Description: Triamterene may increase the excretion rate of Bupropion which could result in a lower serum level and potentially a reduction in efficacy. •Extended Description: The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Triamterene is indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and the nephrotic syndrome; also in steroid-induced edema, idiopathic edema, and edema due to secondary hyperaldosteronism. Triamterene in combination with hydrochlorothiazide is indicated for the managment of hypertension or treatment of edema in patients who develop hypokalemia following hydrochlorothiazide monotherapy, and in patients who require thiazide diuretic and in whom the development of hypokalemia cannot be risked. Triamterene allows the maintenance of potassium balance when given in combination with loop diuretics and thiazides. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Triamterene, a relatively weak, potassium-sparing diuretic and antihypertensive, is used in the management of hypertension and edema. It primarily works on the distal nephron in the kidneys; it acts from the late distal tubule to the collecting duct to inhibit Na+ reabsorption and decreasing K+ excretion. As triamterene tends to conserve potassium more strongly than promoting Na+ excretion, it can cause an increase in serum potassium, which may result in hyperkalemia potentially associated with cardiac irregularities. In healthy volunteers administered with oral triamterene, there was an increase in the renal clearnace of sodium and magnesium, and a decrease in the clearance of uric acid and creatinine due to its effect of reducing glomerular filtration renal plasma flow. Triamterene does not affect calcium excretion. In clinical trials, the use of triamterene in combination with hydrochlorothiazide resulted an enhanced blood pressure-lowering effects of hydrochlorothiazide. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Triamterene inhibits the epithelial sodium channels (ENaC) located on the lumenal side in the late distal convoluted tubule and collecting tubule, which are transmembrane channels that normally promote sodium uptake and potassium secretion. In the late distal tubule to the collecting duct, sodium ions are actively reabsorbed via ENaC on the luminal membrane and are extruded out of the cell into the peritubular medium by a sodium-potassium exchange pump, the Na-K-ATPase, with water following passively. Triamterene exerts a diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium ions in exchange for potassium and hydrogen ions and its natriuretic activity is limited by the amount of sodium reaching its site of action. Its action is antagonistic to that of adrenal mineralocorticoids, such as aldosterone, but it is not an inhibitor or antagonist of aldosterone. Triamterene maintains or increases sodium excretion, thereby increasing the excretion of water, and reducing the excess loss of potassium, hydrogen, and chloride ions by inhibiting the distal tubular exchange mechanism. Due to its diuretic effect, triamterene rapidly and reversibly reduces the lumen-negative transepithelial potential difference by almost completely abolishing Na+ conductance without altering K+ conductance. This reduces the driving force for potassium movement into the tubular lumen and thus decreases potassium excretion. Triamterene is similar in action to amiloride but, unlike amiloride, increases the urinary excretion of magnesium. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Triamterene is shown to be rapidly absorbed in the gastrointestinal tract Its onset of action achiveved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. It is reported that the diuretic effect of triamterene may not be observed for several days after administration. In a pharmacokinetic study, the oral bioavailability of triamterene was determined to be 52%. Following administration of a single oral dose to fasted healthy male volunteers, the mean AUC of triamterene was about 148.7 ng*hr/mL and the mean peak plasma concentrations (Cmax) were 46.4 ng/mL reached at 1.1 hour after administration. In a limited study, administration of triamterene in combination with hydrochlorothiazide resulted in an increased bioavailability of triamterene by about 67% and a delay of up to 2 hours in the absorption of the drug. It is advised that triamterene is administered after meals; in a limited study, combination use of triamterene and hydrochlorothiazide with the consumption of a high-fat meal resulted in an increase in the mean bioavailability and peak serum concentrations of triamterene and its active sulfate metabolite, as well as a delay of up to 2 hours in the absorption of the active constituents. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In a pharmacolinetic study involving healthy volunteers receiving triamterene intravenously, the volumes of distribution of the central compartment of triamterene and its hydroxylated ester metabolite were 1.49 L/kg and 0.11 L/kg, respectively. Triamterene was found to cross the placental barrier and appear in the cord blood of animals. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 67% bound to proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Triamterene undergoes phase I metabolism involving hydroxylation, via CYP1A2 activity, to form 4'-hydroxytriamterene. 4'-Hydroxytriamterene is further transformed in phase II metabolism mediated by cytosolic sulfotransferases to form the major metabolite, 4′-hydroxytriamterene sulfate, which retains a diuretic activity. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels while the renal clearance of the sulfate conjugate was les than that of triamterene; this low renal clearance of the sulfate conjugate as compared with triamterene may be explained by the low unbound fraction of the metabolite in plasma. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Triamterene and its metabolites are excreted by the kidney by filtration and tubular secretion. Upon oral ingestion, somewhat less than 50% of the oral dose reaches the urine. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxytriamterene and 10% as free hydroxytriamterene and triamterene glucuronide. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half-life of the drug in plasma ranges from 1.5 to 2 hours. In a pharmacokinetic study involving healthy volunteers, the terminal half-lives for triamterene and 4′-hydroxytriamterene sulfate were 255 ± 42 and 188 ± 70 minutes, respectively, after intravenous infusion of the parent drug. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total plasma clearance was 4.5 l/min and renal plasma clearance was 0.22 l/kg following intravenous administration of triamterene in healthy volunteers. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Acute oral LD50 of triamterene in rats is 400 mg/kg and 285-380 mg/kg in mice. There has been a case of reversible acute renal failure following ingestion of 50 combination pills containing 50 mg triamterene and 25 mg hydrochlorothiazide. Symptoms of overdose, such as nausea, vomiting, gastrointestinal disturbances, weakness, and hypotension, are related to electrolyte imbalances, such as hyperkalemia. As there is no specific antidote, emesis and gastric lavage should be use to induce immediate evacuation of the stomach and careful evaluation of the electrolyte pattern and fluid balance should be made. Dialysis may be somewhat effective in case of an overdosage. In a carciongenicity study in male and female mice administered with triamterene at the highst dosage level, there was an increased incidence of hepatocellular neoplasia, primarily adenomas. However, this was not a dose-dependent phenomenon and there was no statistically significant difference from control incidence at any dose level. In bacterial assays, there was no demonstrated mutagenic potential of triamterene. In in vitro assay using Chinese hamster ovary (CHO) cells with or without metabolic activation, there were no chromosomal aberrations. Studies evaluating the effects of triamterene on reproductive system or fertility have not been conducted. It is advised that the use of triamterene is avoided during pregnancy. As triamterene has been detected in human breast milk, triamterene should be used when nursing is ceased. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Dyrenium, Maxzide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Teridin Triamteren Triamterena Triamtérène Triamterene Triamtereno Triamterenum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Triamterene is a potassium-sparing diuretic used in the treatment of edema and in the management of hypertension.

The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. The severity of the interaction is moderate.

Question: Does Bupropion and Triamterene interact? Information: •Drug A: Bupropion •Drug B: Triamterene •Severity: MODERATE •Description: Triamterene may increase the excretion rate of Bupropion which could result in a lower serum level and potentially a reduction in efficacy. •Extended Description: The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Triamterene is indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and the nephrotic syndrome; also in steroid-induced edema, idiopathic edema, and edema due to secondary hyperaldosteronism. Triamterene in combination with hydrochlorothiazide is indicated for the managment of hypertension or treatment of edema in patients who develop hypokalemia following hydrochlorothiazide monotherapy, and in patients who require thiazide diuretic and in whom the development of hypokalemia cannot be risked. Triamterene allows the maintenance of potassium balance when given in combination with loop diuretics and thiazides. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Triamterene, a relatively weak, potassium-sparing diuretic and antihypertensive, is used in the management of hypertension and edema. It primarily works on the distal nephron in the kidneys; it acts from the late distal tubule to the collecting duct to inhibit Na+ reabsorption and decreasing K+ excretion. As triamterene tends to conserve potassium more strongly than promoting Na+ excretion, it can cause an increase in serum potassium, which may result in hyperkalemia potentially associated with cardiac irregularities. In healthy volunteers administered with oral triamterene, there was an increase in the renal clearnace of sodium and magnesium, and a decrease in the clearance of uric acid and creatinine due to its effect of reducing glomerular filtration renal plasma flow. Triamterene does not affect calcium excretion. In clinical trials, the use of triamterene in combination with hydrochlorothiazide resulted an enhanced blood pressure-lowering effects of hydrochlorothiazide. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Triamterene inhibits the epithelial sodium channels (ENaC) located on the lumenal side in the late distal convoluted tubule and collecting tubule, which are transmembrane channels that normally promote sodium uptake and potassium secretion. In the late distal tubule to the collecting duct, sodium ions are actively reabsorbed via ENaC on the luminal membrane and are extruded out of the cell into the peritubular medium by a sodium-potassium exchange pump, the Na-K-ATPase, with water following passively. Triamterene exerts a diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium ions in exchange for potassium and hydrogen ions and its natriuretic activity is limited by the amount of sodium reaching its site of action. Its action is antagonistic to that of adrenal mineralocorticoids, such as aldosterone, but it is not an inhibitor or antagonist of aldosterone. Triamterene maintains or increases sodium excretion, thereby increasing the excretion of water, and reducing the excess loss of potassium, hydrogen, and chloride ions by inhibiting the distal tubular exchange mechanism. Due to its diuretic effect, triamterene rapidly and reversibly reduces the lumen-negative transepithelial potential difference by almost completely abolishing Na+ conductance without altering K+ conductance. This reduces the driving force for potassium movement into the tubular lumen and thus decreases potassium excretion. Triamterene is similar in action to amiloride but, unlike amiloride, increases the urinary excretion of magnesium. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Triamterene is shown to be rapidly absorbed in the gastrointestinal tract Its onset of action achiveved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. It is reported that the diuretic effect of triamterene may not be observed for several days after administration. In a pharmacokinetic study, the oral bioavailability of triamterene was determined to be 52%. Following administration of a single oral dose to fasted healthy male volunteers, the mean AUC of triamterene was about 148.7 ng*hr/mL and the mean peak plasma concentrations (Cmax) were 46.4 ng/mL reached at 1.1 hour after administration. In a limited study, administration of triamterene in combination with hydrochlorothiazide resulted in an increased bioavailability of triamterene by about 67% and a delay of up to 2 hours in the absorption of the drug. It is advised that triamterene is administered after meals; in a limited study, combination use of triamterene and hydrochlorothiazide with the consumption of a high-fat meal resulted in an increase in the mean bioavailability and peak serum concentrations of triamterene and its active sulfate metabolite, as well as a delay of up to 2 hours in the absorption of the active constituents. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In a pharmacolinetic study involving healthy volunteers receiving triamterene intravenously, the volumes of distribution of the central compartment of triamterene and its hydroxylated ester metabolite were 1.49 L/kg and 0.11 L/kg, respectively. Triamterene was found to cross the placental barrier and appear in the cord blood of animals. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 67% bound to proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Triamterene undergoes phase I metabolism involving hydroxylation, via CYP1A2 activity, to form 4'-hydroxytriamterene. 4'-Hydroxytriamterene is further transformed in phase II metabolism mediated by cytosolic sulfotransferases to form the major metabolite, 4′-hydroxytriamterene sulfate, which retains a diuretic activity. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels while the renal clearance of the sulfate conjugate was les than that of triamterene; this low renal clearance of the sulfate conjugate as compared with triamterene may be explained by the low unbound fraction of the metabolite in plasma. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Triamterene and its metabolites are excreted by the kidney by filtration and tubular secretion. Upon oral ingestion, somewhat less than 50% of the oral dose reaches the urine. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxytriamterene and 10% as free hydroxytriamterene and triamterene glucuronide. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half-life of the drug in plasma ranges from 1.5 to 2 hours. In a pharmacokinetic study involving healthy volunteers, the terminal half-lives for triamterene and 4′-hydroxytriamterene sulfate were 255 ± 42 and 188 ± 70 minutes, respectively, after intravenous infusion of the parent drug. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total plasma clearance was 4.5 l/min and renal plasma clearance was 0.22 l/kg following intravenous administration of triamterene in healthy volunteers. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Acute oral LD50 of triamterene in rats is 400 mg/kg and 285-380 mg/kg in mice. There has been a case of reversible acute renal failure following ingestion of 50 combination pills containing 50 mg triamterene and 25 mg hydrochlorothiazide. Symptoms of overdose, such as nausea, vomiting, gastrointestinal disturbances, weakness, and hypotension, are related to electrolyte imbalances, such as hyperkalemia. As there is no specific antidote, emesis and gastric lavage should be use to induce immediate evacuation of the stomach and careful evaluation of the electrolyte pattern and fluid balance should be made. Dialysis may be somewhat effective in case of an overdosage. In a carciongenicity study in male and female mice administered with triamterene at the highst dosage level, there was an increased incidence of hepatocellular neoplasia, primarily adenomas. However, this was not a dose-dependent phenomenon and there was no statistically significant difference from control incidence at any dose level. In bacterial assays, there was no demonstrated mutagenic potential of triamterene. In in vitro assay using Chinese hamster ovary (CHO) cells with or without metabolic activation, there were no chromosomal aberrations. Studies evaluating the effects of triamterene on reproductive system or fertility have not been conducted. It is advised that the use of triamterene is avoided during pregnancy. As triamterene has been detected in human breast milk, triamterene should be used when nursing is ceased. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Dyrenium, Maxzide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Teridin Triamteren Triamterena Triamtérène Triamterene Triamtereno Triamterenum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Triamterene is a potassium-sparing diuretic used in the treatment of edema and in the management of hypertension. Output: The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. The severity of the interaction is moderate.

Does Bupropion and Triazolam interact?

•Drug A: Bupropion •Drug B: Triazolam •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Triazolam is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the short-term treatment of insomnia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): A short-acting benzodiazepine used as a hypnotic agent in the treatment of insomnia. Some countries temporarily withdrew triazolam from the market because of concerns about adverse reactions, mostly psychological, associated with higher dose ranges. Its use at lower doses with appropriate care and labeling has been reaffirmed by the FDA and most other countries. Triazolam has a shorter half-life than chlordiazepoxide, flurazepam, and prazepam and does not generate active metabolites. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Benzodiazepines bind nonspecifically to bezodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA A ) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Bioavailability is 44% (oral) and 53% (sublingual). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. Small amounts of unmetabolized triazolam appear in the urine. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Triazolam and its metabolites, principally as conjugated glucuronides, which are presumably inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites accounted for 79.9% of urinary excretion. •Half-life (Drug A): 24 hours •Half-life (Drug B): 1.5-5.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include drowsiness, slurred speech, motor inco-ordination, coma, and respiratory depression. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Halcion •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Triazolam is a benzodiazepine used for short term treatment of insomnia.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Triazolam interact? Information: •Drug A: Bupropion •Drug B: Triazolam •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Triazolam is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the short-term treatment of insomnia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): A short-acting benzodiazepine used as a hypnotic agent in the treatment of insomnia. Some countries temporarily withdrew triazolam from the market because of concerns about adverse reactions, mostly psychological, associated with higher dose ranges. Its use at lower doses with appropriate care and labeling has been reaffirmed by the FDA and most other countries. Triazolam has a shorter half-life than chlordiazepoxide, flurazepam, and prazepam and does not generate active metabolites. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Benzodiazepines bind nonspecifically to bezodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA A ) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Bioavailability is 44% (oral) and 53% (sublingual). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. Small amounts of unmetabolized triazolam appear in the urine. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Triazolam and its metabolites, principally as conjugated glucuronides, which are presumably inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites accounted for 79.9% of urinary excretion. •Half-life (Drug A): 24 hours •Half-life (Drug B): 1.5-5.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include drowsiness, slurred speech, motor inco-ordination, coma, and respiratory depression. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Halcion •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Triazolam is a benzodiazepine used for short term treatment of insomnia. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Triclabendazole interact?

•Drug A: Bupropion •Drug B: Triclabendazole •Severity: MINOR •Description: The serum concentration of Bupropion can be increased when it is combined with Triclabendazole. •Extended Description: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): This drug is indicated for the treatment of fascioliasis in patients aged 6 years old and above. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Triclabendazole and its metabolites are active against both the immature and mature worms of Fasciola hepatica and Fasciola gigantica helminths. Effect on QT interval This drug may prolong the cardiac QT interval. Monitor ECG in patients with a history of QT prolongation or who are taking medications known to prolong the QT interval. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Triclabendazole is an anthelmintic agent against Fasciola species. The mechanism of action against Fasciola species is not fully understood at this time. In vitro studies and animal studies suggest that triclabendazole and its active metabolites ( sulfoxide and sulfone ) are absorbed by the outer body covering of the immature and mature worms, causing a reduction in the resting membrane potential, the inhibition of tubulin function as well as protein and enzyme synthesis necessary for survival. These metabolic disturbances lead to an inhibition of motility, disruption of the worm outer surface, in addition to the inhibition of spermatogenesis and egg/embryonic cells. A note on resistance In vitro studies, in vivo studies, as well as case reports suggest a possibility for the development of resistance to triclabendazole. The mechanism of resistance may be multifactorial and include changes in drug uptake/efflux mechanisms, target molecules, and changes in drug metabolism. The clinical significance of triclabendazole resistance in humans is not yet elucidated. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After a single oral dose of 10 mg/kg triclabendazole with a 560-kcal meal to patients diagnosed with fascioliasis, mean peak plasma concentrations (Cmax) for triclabendazole, the sulfoxide, and sulfone metabolites were 1.16, 38.6, and 2.29 μmol/L, respectively. The area under the curve (AUC) for triclabendazole, the sulfoxide and sulfone metabolites were 5.72, 386, and 30.5 μmol∙h/L, respectively. After the oral administration of a single dose of triclabendazole at 10 mg/kg with a 560 calorie meal to patients with fascioliasis, the median Tmax for the parent compound as well as the active sulfoxide metabolite was 3 to 4 hours. Effect of Food Cmax and AUC of triclabendazole and sulfoxide metabolite increased about 2-3 times when triclabendazole was administered as a single dose at 10 mg/kg with a meal containing approximately 560 calories. Additionally, the sulfoxide metabolite Tmax increased from 2 hours in fasting subjects to 4 hours in fed subjects. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution (Vd) of the sulfoxide metabolite in fed patients is about 1 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Protein-binding of triclabendazole, sulfoxide metabolite and sulfone metabolite in human plasma was 96.7%, 98.4% and 98.8% respectively. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Based on in vitro studies, triclabendazole is mainly metabolized by CYP1A2 enzyme (approximately 64%) into its active sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO (flavin containing monooxygenase). This sulfoxide metabolite is further metabolized mainly by CYP2C9 to the active sulfone metabolite, and to a smaller extent by CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4, in vitro. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No data regarding excretion is available in humans. In animals, triclabendazole is primarily excreted by the biliary tract in the feces (90%), together with the sulfoxide and sulfone metabolite. Less than 10% of an oral dose is found excreted in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The plasma elimination half-life (t1/2) of triclabendazole, the sulfoxide and sulfone metabolites in human is about 8, 14, and 11 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral LD50 (rat): >8 gm/kg; Oral LD50 (mouse): >8 gm/kg A note on the use in pregnancy There are no available data on triclabendazole use in pregnant women to calculate a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Reproductive studies in animals (rat and rabbits) have not demonstrated an increased risk of increased fetal abnormalities with exposure to triclabendazole during the organogenesis period at doses which were about 0.3 to 1.6 times the maximum recommended human dose (MRHD) of 20 mg/kg. Carcinogenesis/Mutagenesis No genotoxic risk was noted for triclabendazole tested in 6 genotoxicity in vitro and in vivo assays. Impairment of Fertility No drug-related effects on reproductive performance, mating ratios or indices of fertility have been observed in a 2-generation reproductive and developmental toxicity study in rats. A note on use in breastfeeding There are no human findings on the presence of triclabendazole in milk, the effects on a nursing infant, or the effects on maternal milk production. The results of animal studies indicate that triclabendazole is found in goat milk when given as a single dose to a lactating female goat. When a drug is found to be present in animal milk, the likelihood that it will be found in human milk is high. Excercise caution if this drug is administered during nursing. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Egaten •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Triclabendazole is an anthelmintic drug used to treat fascioliasis.

Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. The severity of the interaction is minor.

Question: Does Bupropion and Triclabendazole interact? Information: •Drug A: Bupropion •Drug B: Triclabendazole •Severity: MINOR •Description: The serum concentration of Bupropion can be increased when it is combined with Triclabendazole. •Extended Description: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): This drug is indicated for the treatment of fascioliasis in patients aged 6 years old and above. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Triclabendazole and its metabolites are active against both the immature and mature worms of Fasciola hepatica and Fasciola gigantica helminths. Effect on QT interval This drug may prolong the cardiac QT interval. Monitor ECG in patients with a history of QT prolongation or who are taking medications known to prolong the QT interval. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Triclabendazole is an anthelmintic agent against Fasciola species. The mechanism of action against Fasciola species is not fully understood at this time. In vitro studies and animal studies suggest that triclabendazole and its active metabolites ( sulfoxide and sulfone ) are absorbed by the outer body covering of the immature and mature worms, causing a reduction in the resting membrane potential, the inhibition of tubulin function as well as protein and enzyme synthesis necessary for survival. These metabolic disturbances lead to an inhibition of motility, disruption of the worm outer surface, in addition to the inhibition of spermatogenesis and egg/embryonic cells. A note on resistance In vitro studies, in vivo studies, as well as case reports suggest a possibility for the development of resistance to triclabendazole. The mechanism of resistance may be multifactorial and include changes in drug uptake/efflux mechanisms, target molecules, and changes in drug metabolism. The clinical significance of triclabendazole resistance in humans is not yet elucidated. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After a single oral dose of 10 mg/kg triclabendazole with a 560-kcal meal to patients diagnosed with fascioliasis, mean peak plasma concentrations (Cmax) for triclabendazole, the sulfoxide, and sulfone metabolites were 1.16, 38.6, and 2.29 μmol/L, respectively. The area under the curve (AUC) for triclabendazole, the sulfoxide and sulfone metabolites were 5.72, 386, and 30.5 μmol∙h/L, respectively. After the oral administration of a single dose of triclabendazole at 10 mg/kg with a 560 calorie meal to patients with fascioliasis, the median Tmax for the parent compound as well as the active sulfoxide metabolite was 3 to 4 hours. Effect of Food Cmax and AUC of triclabendazole and sulfoxide metabolite increased about 2-3 times when triclabendazole was administered as a single dose at 10 mg/kg with a meal containing approximately 560 calories. Additionally, the sulfoxide metabolite Tmax increased from 2 hours in fasting subjects to 4 hours in fed subjects. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution (Vd) of the sulfoxide metabolite in fed patients is about 1 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Protein-binding of triclabendazole, sulfoxide metabolite and sulfone metabolite in human plasma was 96.7%, 98.4% and 98.8% respectively. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Based on in vitro studies, triclabendazole is mainly metabolized by CYP1A2 enzyme (approximately 64%) into its active sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO (flavin containing monooxygenase). This sulfoxide metabolite is further metabolized mainly by CYP2C9 to the active sulfone metabolite, and to a smaller extent by CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4, in vitro. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No data regarding excretion is available in humans. In animals, triclabendazole is primarily excreted by the biliary tract in the feces (90%), together with the sulfoxide and sulfone metabolite. Less than 10% of an oral dose is found excreted in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The plasma elimination half-life (t1/2) of triclabendazole, the sulfoxide and sulfone metabolites in human is about 8, 14, and 11 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral LD50 (rat): >8 gm/kg; Oral LD50 (mouse): >8 gm/kg A note on the use in pregnancy There are no available data on triclabendazole use in pregnant women to calculate a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Reproductive studies in animals (rat and rabbits) have not demonstrated an increased risk of increased fetal abnormalities with exposure to triclabendazole during the organogenesis period at doses which were about 0.3 to 1.6 times the maximum recommended human dose (MRHD) of 20 mg/kg. Carcinogenesis/Mutagenesis No genotoxic risk was noted for triclabendazole tested in 6 genotoxicity in vitro and in vivo assays. Impairment of Fertility No drug-related effects on reproductive performance, mating ratios or indices of fertility have been observed in a 2-generation reproductive and developmental toxicity study in rats. A note on use in breastfeeding There are no human findings on the presence of triclabendazole in milk, the effects on a nursing infant, or the effects on maternal milk production. The results of animal studies indicate that triclabendazole is found in goat milk when given as a single dose to a lactating female goat. When a drug is found to be present in animal milk, the likelihood that it will be found in human milk is high. Excercise caution if this drug is administered during nursing. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Egaten •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Triclabendazole is an anthelmintic drug used to treat fascioliasis. Output: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. The severity of the interaction is minor.

Does Bupropion and Triethylenetetramine interact?

•Drug A: Bupropion •Drug B: Triethylenetetramine •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Triethylenetetramine is a copper chelator indicated for the treatment of adult patients with stable Wilson’s disease who are de-coppered and tolerant to penicillamine. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Triethylenetetramine (TETA) is a selective copper(II) chelator that works to promote urinary copper excretion. It was shown to reduce excess body copper storage and ameliorate symptoms of Wilson’s disease. In rats with diabetes mellitus, intravenous administration of TETA led to a dose-dependent increase in urinary copper excretion. In preliminary studies, TETA was shown to ameliorate left ventricular hypertrophy in both human and animal subjects with diabetes. In animal models, TETA was also shown to reverse manifestations of diabetic nephropathy, including nephromegaly, renal fibrosis, glomerulosclerosis, and albuminuria, without lowering hyperglycemia. This finding may be explained by TETA chelating copper cations, which are pro-oxidant and activate pathways that produce excessive reactive oxygen species (ROS) that cause tissue injury. TETA was shown to possess anti-angiogenesis properties, as copper is an essential element for angiogenesis in cancer cells. TETA was shown to inhibit telomerase, suggesting that it may exhibit an inhibitory effect or cytotoxicity on tumor growth. Based on these early findings, TETA has been studied for its anticancer effects. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Wilson's disease is an autosomal recessive genetic disorder that leads to copper accumulation in the tissues. It is characterized by an array of neurologic or psychiatric symptoms as well as liver disease. One of the treatments for Wilson's disease is the use of copper-chelating agents, such as triethylenetetramine (TETA). TETA forms a stable complex with copper(II), which is then is readily eliminated through urinary excretion. TETA also chelates copper in the intestinal tract, reducing intestinal copper absorption by 80%. TETA and its metabolite, N 1 -acetyltriethylenetetramine (MAT), are also capable of binding divalent iron, divalent zinc, magnesium, and manganese. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): TETA is poorly absorbed from the gastrointestinal tract with an oral bioavailability ranging from 6% to 18%. TETA has the potential to chelate non-copper cations in mineral supplements and other oral drugs, resulting in altered drug absorption; thus, TETA should be administered at least one hour apart from these medications. The median T max ranges from 1.25 to 2 hours. Mean C max (± SD) of triethylenetetramine (TETA) was 2030 ± 981 ng/mL following oral administration of 900 mg TETA and 3430 ± 1480 ng/mL following administration of 1500 mg TETA. The systemic exposure (AUC) of TETA increased in a dose-proportional manner over the range of 900 mg to 1500 mg TETA. The mean AUC inf (± SD) was 9750 ± 4910 ngxh/mL at 900 mg and 17200 ± 9470 ngxh/mL at 1500 mg. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): TETA is widely distributed in tissues, with relatively high concentrations measured in liver, heart, and kidney. It is prone to accumulation in certain tissues. In healthy adult volunteers receiving oral capsules of TETA, the apparent volume of distribution of steady state was 645 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The majority of absorbed TETA is extensively metabolized into acetyl-metabolites. TETA undergoes acetylation mediated by diamine acetyltransferase, also known as spermidine/spermine N 1 -acetyltranferase, to form two major active metabolites, N 1 -acetyltriethylenetetramine (MAT) and N 1,N 10 -diacetyltriethylenetetramine (DAT). The chelating activity of MAT is significantly lower than that of TETA. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): TETA and its metabolites, MAT and DAT, are mainly excreted in the urine. Approximately less than 1% of the administered dose is renally excreted as unchanged drug within the first six hours of dosing. About 8% of the dose is excreted as two major metabolites of TETA, MAT and DAT. Urinary excretion of metabolites occurs later than the excretion of the unchanged parent drug: it continues for 26 hours or longer. •Half-life (Drug A): 24 hours •Half-life (Drug B): The mean terminal half-life (t1/2) ranged from 13.8 to 16.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In healthy adult volunteers receiving oral capsules of TETA, the oral total clearance was 69.5 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 was 2500 mg/kg in rats. The dermal LD 50 was 550 mg/kg in rabbits. Occasional cases of trientine overdose have been reported. A large overdose of 60 g of trientine hydrochloride resulted in nausea, vomiting, dizziness, mild acute kidney injury, mild hypophosphatemia, low serum zinc, and low serum copper: the patient recovered following intravenous hydration and supportive measures. There is no antidote for an acute overdose from trientine. Chronic use of trientine at dosages above the maximum recommended dosage has resulted in sideroblastic anemia. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Cuvrior, Syprine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Triethylenetetramine is a copper chelating agent used for the management of Wilson's disease in cases where penicillamine therapy is clinically inappropriate.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Triethylenetetramine interact? Information: •Drug A: Bupropion •Drug B: Triethylenetetramine •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Triethylenetetramine is a copper chelator indicated for the treatment of adult patients with stable Wilson’s disease who are de-coppered and tolerant to penicillamine. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Triethylenetetramine (TETA) is a selective copper(II) chelator that works to promote urinary copper excretion. It was shown to reduce excess body copper storage and ameliorate symptoms of Wilson’s disease. In rats with diabetes mellitus, intravenous administration of TETA led to a dose-dependent increase in urinary copper excretion. In preliminary studies, TETA was shown to ameliorate left ventricular hypertrophy in both human and animal subjects with diabetes. In animal models, TETA was also shown to reverse manifestations of diabetic nephropathy, including nephromegaly, renal fibrosis, glomerulosclerosis, and albuminuria, without lowering hyperglycemia. This finding may be explained by TETA chelating copper cations, which are pro-oxidant and activate pathways that produce excessive reactive oxygen species (ROS) that cause tissue injury. TETA was shown to possess anti-angiogenesis properties, as copper is an essential element for angiogenesis in cancer cells. TETA was shown to inhibit telomerase, suggesting that it may exhibit an inhibitory effect or cytotoxicity on tumor growth. Based on these early findings, TETA has been studied for its anticancer effects. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Wilson's disease is an autosomal recessive genetic disorder that leads to copper accumulation in the tissues. It is characterized by an array of neurologic or psychiatric symptoms as well as liver disease. One of the treatments for Wilson's disease is the use of copper-chelating agents, such as triethylenetetramine (TETA). TETA forms a stable complex with copper(II), which is then is readily eliminated through urinary excretion. TETA also chelates copper in the intestinal tract, reducing intestinal copper absorption by 80%. TETA and its metabolite, N 1 -acetyltriethylenetetramine (MAT), are also capable of binding divalent iron, divalent zinc, magnesium, and manganese. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): TETA is poorly absorbed from the gastrointestinal tract with an oral bioavailability ranging from 6% to 18%. TETA has the potential to chelate non-copper cations in mineral supplements and other oral drugs, resulting in altered drug absorption; thus, TETA should be administered at least one hour apart from these medications. The median T max ranges from 1.25 to 2 hours. Mean C max (± SD) of triethylenetetramine (TETA) was 2030 ± 981 ng/mL following oral administration of 900 mg TETA and 3430 ± 1480 ng/mL following administration of 1500 mg TETA. The systemic exposure (AUC) of TETA increased in a dose-proportional manner over the range of 900 mg to 1500 mg TETA. The mean AUC inf (± SD) was 9750 ± 4910 ngxh/mL at 900 mg and 17200 ± 9470 ngxh/mL at 1500 mg. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): TETA is widely distributed in tissues, with relatively high concentrations measured in liver, heart, and kidney. It is prone to accumulation in certain tissues. In healthy adult volunteers receiving oral capsules of TETA, the apparent volume of distribution of steady state was 645 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The majority of absorbed TETA is extensively metabolized into acetyl-metabolites. TETA undergoes acetylation mediated by diamine acetyltransferase, also known as spermidine/spermine N 1 -acetyltranferase, to form two major active metabolites, N 1 -acetyltriethylenetetramine (MAT) and N 1,N 10 -diacetyltriethylenetetramine (DAT). The chelating activity of MAT is significantly lower than that of TETA. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): TETA and its metabolites, MAT and DAT, are mainly excreted in the urine. Approximately less than 1% of the administered dose is renally excreted as unchanged drug within the first six hours of dosing. About 8% of the dose is excreted as two major metabolites of TETA, MAT and DAT. Urinary excretion of metabolites occurs later than the excretion of the unchanged parent drug: it continues for 26 hours or longer. •Half-life (Drug A): 24 hours •Half-life (Drug B): The mean terminal half-life (t1/2) ranged from 13.8 to 16.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In healthy adult volunteers receiving oral capsules of TETA, the oral total clearance was 69.5 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 was 2500 mg/kg in rats. The dermal LD 50 was 550 mg/kg in rabbits. Occasional cases of trientine overdose have been reported. A large overdose of 60 g of trientine hydrochloride resulted in nausea, vomiting, dizziness, mild acute kidney injury, mild hypophosphatemia, low serum zinc, and low serum copper: the patient recovered following intravenous hydration and supportive measures. There is no antidote for an acute overdose from trientine. Chronic use of trientine at dosages above the maximum recommended dosage has resulted in sideroblastic anemia. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Cuvrior, Syprine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Triethylenetetramine is a copper chelating agent used for the management of Wilson's disease in cases where penicillamine therapy is clinically inappropriate. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Trifluoperazine interact?

•Drug A: Bupropion •Drug B: Trifluoperazine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Trifluoperazine is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of anxiety disorders, depressive symptoms secondary to anxiety and agitation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trifluoperazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Trifluoperazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Trifluoperazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 10-20 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, and restlessness. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trifluoperazina Trifluoperazine Trifluopérazine Trifluoperazinum Trifluoroperazine Trifluperazine •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trifluoperazine is a phenothiazine used to treat depression, anxiety, and agitation.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Trifluoperazine interact? Information: •Drug A: Bupropion •Drug B: Trifluoperazine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Trifluoperazine is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of anxiety disorders, depressive symptoms secondary to anxiety and agitation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trifluoperazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Trifluoperazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Trifluoperazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 10-20 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, and restlessness. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trifluoperazina Trifluoperazine Trifluopérazine Trifluoperazinum Trifluoroperazine Trifluperazine •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trifluoperazine is a phenothiazine used to treat depression, anxiety, and agitation. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Trifluridine interact?

•Drug A: Bupropion •Drug B: Trifluridine •Severity: MINOR •Description: Trifluridine may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): As a standalone product, trifluridine is used for the ophthalmic treatment of primay keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2. Trifluridine is also available as a combination product with tipiracil, which is indicated either alone or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. This combination product is also used for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma and were previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trifluridine exhibits an antiviral effect against herpes simplex virus, types 1 and 2 and vacciniavirus both in vitro and in vivo. Some strains of adenovirus that contribute to the pathology of keratoconjunctivitis were shown to be susceptible to trifluridine in vitro. While there is evidence from a study that cross-resistance may develop between trifluridine and idoxuridine or vidarabine, trifluridine was shown to effective in treating dendritic ulcers in patients with herpetic keratitis who are unresponsive to idoxuridine or vidarabine based on the results from masked comparative trials. In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity against both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines. The cytotoxic activity of trifluridine and tipiracil against several human tumour xenografts show high correlation with the amount of trifluridine incorporated into DNA, indicating that the primary mechanism of action of trifluridine involves the direct incorporation into the cancer cell DNA. Trifluridine and tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice. In clinical studies comprised of patients with previously treated metastatic colorectal cancer, treatment of trifluridine in combination with tipiracil in addition to best supportive care over a 5- or 7-month period resulted in increased progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) compared to placebo. In an open-label study, administration of trifluridine at the recommended dosage in patients with advanced solid tumors had no clinically relevant effect on QT/QTc prolongation compared with placebo. Two out of 48 patients displayed had QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of trifluridine as an antiviral agent has not been fully elucidated, but appears to involve the inhibition of viral replication. Trifluridine gets incorporated into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate. Trifluridine also mediates antineoplastic activities via this mechanism; following uptake into cancer cells, trifluridine is rapidly phosphorylated by thymidine kinase to its active monophosphate form. Subsequent phosphorylation produces trifluridine triphosphate, which is readily incorporated into the DNA of tumour cells in place of thymidine bases to perturb DNA function, DNA synthesis, and tumour cell proliferation. As trifluridine is subject to rapid degradation by TPase and readily metabolised by a first-pass effect following oral administration, tipiracil is added in the antineoplastic combination product as an inhibitor of TPase to increase the bioavailability of trifluridine. Trifluridine monophosphate also reversibly inhibits thymidylate synthetase (TS), an enzyme that is necessary for DNA synthesis and which levels are shown to be elevated different cancer cell lines. Up-regulation of the expression of the TS enzyme may also lead to the resistance to antineoplastic therapies, such as 5-fluorouracil (5-FU). [A35289 However, this inhibitory effect is not considered to be sufficient enough to fully contribute to the cytotoxicity in cancer cells. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After oral administration of LONSURF with [14C]-trifluridine, at least 57% of the administered trifluridine was absorbed. Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumors, the mean times to peak plasma concentrations (T max ) of trifluridine was around 2 hours. Trifluridine area under the concentration-time curve from time 0 to the last measurable concentration (AUC 0-last ) was approximately 3-fold higher and maximum concentration (C max ) was approximately 2-fold higher after multiple dose administration (twice daily for 5 days a week with 2 days rest for 2 weeks followed by a 14-day rest, repeated every 4 weeks) than after single-dose administration. Following a single oral administration of LONSURF at 35 mg/m in patients with cancer, the mean time to peak plasma concentration (T max ) of trifluridine was around 2 hours. For the ophthalmic formulation, systemic absorption appears to be negligible. A standardized high-fat, high-calorie meal decreased trifluridine C max by approximately 40% but did not change trifluridine AUC compared to those in a fasting state in patients with cancer following administration of a single dose of LONSURF 35 mg/m. In a dose finding study (15 to 35 mg/m twice daily), the AUC from time 0 to 10 hours (AUC0-10) of trifluridine tended to increase more than expected based on the increase in dose. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for trifluridine was 21 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): In vitro findings suggest that the protein binding of trifluridine in human plasma is greater than 96%, where it is mainly bound to human serum albumin. Protein binding of trifluridine is independent of drug concentration and presence of tipiracil. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Trifluridine is not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY). No other major metabolites were detected in plasma or urine. Other minor metabolites, such as 5-carboxy-2'-deoxyuridine found on the endothelial side of the cornea or 5-carboxyuraci, were also detected, but only at low or trace level in plasma and urine. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): After single oral administration of LONSURF (60 mg) with [14C]-trifluridine, the total cumulative excretion of radioactivity was 60% of the administered dose. The majority of recovered radioactivity was eliminated into urine (55% of the dose) as FTY and trifluridine glucuronide isomers within 24 hours and the excretion into feces and expired air was <3% for both. The unchanged trifluridine was <3% of administered dose recovered in the urine and feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): After administration of LONSURF 35 mg/m, the mean elimination and steady-state half-life (t 1/2 ) of trifluridine was 1.4 hours and 2.1 hours respectively. For the ophthalmic formulation, the half-life is significantly shorter, approximately only 12 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumours, the oral clearance (CL/F) for trifluridine was 10.5 L/hr. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Intravenous LD50 in rat was 2946 mg/kg. Oral LD50 in rat and mouse were > 4379mg/kg. Overdosage via ocular instillation is unlikely. The highest dose of orally-administered Lonsurf, trifluridine in combination with tipiracil, administered in clinical studies was 180 mg/m^2 per day. The primary anticipated complication of an overdose is bone marrow suppression. There is no known antidote for trifluridine overdose: in case of an overdose, management should include customary therapeutic and supportive medical intervention aimed at correcting the presenting clinical manifestations and preventing their possible complications. Based on the findings from animal studies, trifluridine may cause fetal toxicity when administered to pregnant patients. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Lonsurf, Viroptic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trifluoromethyldeoxyuridine Trifluorothymidine Trifluorothymine deoxyriboside Trifluridin Trifluridina Trifluridine Trifluridinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trifluridine is a nucleoside metabolic inhibitor used to treat keratoconjunctivitis and epithelial keratitis caused by simplex virus, and as a part of chemotherapy for certain types of metastatic gastrointestinal cancers.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Trifluridine interact? Information: •Drug A: Bupropion •Drug B: Trifluridine •Severity: MINOR •Description: Trifluridine may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): As a standalone product, trifluridine is used for the ophthalmic treatment of primay keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2. Trifluridine is also available as a combination product with tipiracil, which is indicated either alone or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. This combination product is also used for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma and were previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trifluridine exhibits an antiviral effect against herpes simplex virus, types 1 and 2 and vacciniavirus both in vitro and in vivo. Some strains of adenovirus that contribute to the pathology of keratoconjunctivitis were shown to be susceptible to trifluridine in vitro. While there is evidence from a study that cross-resistance may develop between trifluridine and idoxuridine or vidarabine, trifluridine was shown to effective in treating dendritic ulcers in patients with herpetic keratitis who are unresponsive to idoxuridine or vidarabine based on the results from masked comparative trials. In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity against both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines. The cytotoxic activity of trifluridine and tipiracil against several human tumour xenografts show high correlation with the amount of trifluridine incorporated into DNA, indicating that the primary mechanism of action of trifluridine involves the direct incorporation into the cancer cell DNA. Trifluridine and tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice. In clinical studies comprised of patients with previously treated metastatic colorectal cancer, treatment of trifluridine in combination with tipiracil in addition to best supportive care over a 5- or 7-month period resulted in increased progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) compared to placebo. In an open-label study, administration of trifluridine at the recommended dosage in patients with advanced solid tumors had no clinically relevant effect on QT/QTc prolongation compared with placebo. Two out of 48 patients displayed had QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of trifluridine as an antiviral agent has not been fully elucidated, but appears to involve the inhibition of viral replication. Trifluridine gets incorporated into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate. Trifluridine also mediates antineoplastic activities via this mechanism; following uptake into cancer cells, trifluridine is rapidly phosphorylated by thymidine kinase to its active monophosphate form. Subsequent phosphorylation produces trifluridine triphosphate, which is readily incorporated into the DNA of tumour cells in place of thymidine bases to perturb DNA function, DNA synthesis, and tumour cell proliferation. As trifluridine is subject to rapid degradation by TPase and readily metabolised by a first-pass effect following oral administration, tipiracil is added in the antineoplastic combination product as an inhibitor of TPase to increase the bioavailability of trifluridine. Trifluridine monophosphate also reversibly inhibits thymidylate synthetase (TS), an enzyme that is necessary for DNA synthesis and which levels are shown to be elevated different cancer cell lines. Up-regulation of the expression of the TS enzyme may also lead to the resistance to antineoplastic therapies, such as 5-fluorouracil (5-FU). [A35289 However, this inhibitory effect is not considered to be sufficient enough to fully contribute to the cytotoxicity in cancer cells. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After oral administration of LONSURF with [14C]-trifluridine, at least 57% of the administered trifluridine was absorbed. Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumors, the mean times to peak plasma concentrations (T max ) of trifluridine was around 2 hours. Trifluridine area under the concentration-time curve from time 0 to the last measurable concentration (AUC 0-last ) was approximately 3-fold higher and maximum concentration (C max ) was approximately 2-fold higher after multiple dose administration (twice daily for 5 days a week with 2 days rest for 2 weeks followed by a 14-day rest, repeated every 4 weeks) than after single-dose administration. Following a single oral administration of LONSURF at 35 mg/m in patients with cancer, the mean time to peak plasma concentration (T max ) of trifluridine was around 2 hours. For the ophthalmic formulation, systemic absorption appears to be negligible. A standardized high-fat, high-calorie meal decreased trifluridine C max by approximately 40% but did not change trifluridine AUC compared to those in a fasting state in patients with cancer following administration of a single dose of LONSURF 35 mg/m. In a dose finding study (15 to 35 mg/m twice daily), the AUC from time 0 to 10 hours (AUC0-10) of trifluridine tended to increase more than expected based on the increase in dose. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for trifluridine was 21 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): In vitro findings suggest that the protein binding of trifluridine in human plasma is greater than 96%, where it is mainly bound to human serum albumin. Protein binding of trifluridine is independent of drug concentration and presence of tipiracil. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Trifluridine is not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY). No other major metabolites were detected in plasma or urine. Other minor metabolites, such as 5-carboxy-2'-deoxyuridine found on the endothelial side of the cornea or 5-carboxyuraci, were also detected, but only at low or trace level in plasma and urine. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): After single oral administration of LONSURF (60 mg) with [14C]-trifluridine, the total cumulative excretion of radioactivity was 60% of the administered dose. The majority of recovered radioactivity was eliminated into urine (55% of the dose) as FTY and trifluridine glucuronide isomers within 24 hours and the excretion into feces and expired air was <3% for both. The unchanged trifluridine was <3% of administered dose recovered in the urine and feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): After administration of LONSURF 35 mg/m, the mean elimination and steady-state half-life (t 1/2 ) of trifluridine was 1.4 hours and 2.1 hours respectively. For the ophthalmic formulation, the half-life is significantly shorter, approximately only 12 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumours, the oral clearance (CL/F) for trifluridine was 10.5 L/hr. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Intravenous LD50 in rat was 2946 mg/kg. Oral LD50 in rat and mouse were > 4379mg/kg. Overdosage via ocular instillation is unlikely. The highest dose of orally-administered Lonsurf, trifluridine in combination with tipiracil, administered in clinical studies was 180 mg/m^2 per day. The primary anticipated complication of an overdose is bone marrow suppression. There is no known antidote for trifluridine overdose: in case of an overdose, management should include customary therapeutic and supportive medical intervention aimed at correcting the presenting clinical manifestations and preventing their possible complications. Based on the findings from animal studies, trifluridine may cause fetal toxicity when administered to pregnant patients. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Lonsurf, Viroptic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trifluoromethyldeoxyuridine Trifluorothymidine Trifluorothymine deoxyriboside Trifluridin Trifluridina Trifluridine Trifluridinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trifluridine is a nucleoside metabolic inhibitor used to treat keratoconjunctivitis and epithelial keratitis caused by simplex virus, and as a part of chemotherapy for certain types of metastatic gastrointestinal cancers. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Trihexyphenidyl interact?

•Drug A: Bupropion •Drug B: Trihexyphenidyl •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Bupropion is combined with Trihexyphenidyl. •Extended Description: Despite the fact that these drugs are sometimes used in combination to treat depression in Parkinson's disease3, the administration of bupropion with anti-Parkinson drugs may lead to central nervous system toxicity. Bupropion is considered a norepinephrine-dopamine reuptake inhibitor, is found to occupy the DAT dopamine transporter, and acts as a dopamine agonist. Additive effects of these dopaminergic drugs may produce excess dopaminergic activity. Agitation, restlessness, tremor, ataxia, gait disturbance, and dizziness are some examples of effects that may occur from concurrent administration. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tihexyphenidyl is indicated as an adjunct in the treatment of parkinsonism, an adjuvant in the treatment of parkinsonism with levodopa, and in the control of extrapyramidal disorders caused by central nervous system drugs. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trihexyphenidyl is an antimuscarinic indicated as an adjunct in the treatment of parkinsonism or as a treatment for drug-induced extrapyramidal symptoms. It has a long duration of action as it does not need to be given every day. It has a wide therapeutic window, with acute toxicity being non fatal in doses as high as 300 mg. Patients should have their iridocorneal angle examined before and intraocular pressure monitored during therapy. Patients should be counselled regarding the risk of anhidrosis and hyperthermia. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Trihexyphenidyl is a non-selective muscarinic acetylcholine receptor antagonist but binds with higher affinity to the M1 subtype. In vivo studies have shown that trihexyphenidyl demonstrates higher affinity for central muscarinic receptors located in the cerebral cortex and lower affinity for those located peripherally. Other studies suggest that trihexyphenidyl may modify nicotinic acetylcholine receptor neurotransmission, leading indirectly to enhanced dopamine release in the striatum. Although the anticholinergic has proven to be useful in the treatment of symptoms associated with Parkinson’s disease or other movement disorders, its mechanism of action has yet to be fully elucidated. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Trihexyphenidyl is absorbed from the gastrointestinal tract. Trihexyphenidyl reaches a C max of 7.2 ng/mL, with a T max of 1.3 hours, and an AUC of 201 ng*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Data regarding the extent of trihexyphenidyl protein binding in plasma are not readily available. Trihexyphenidyl is 36.13-41.92% bound to albumin under controlled conditions in a dialysis bag. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Data regarding the metabolism of trihexyphenidyl are not readily available. However, it is likely not heavily metabolized. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Data regarding the route of elimination of trihexyphenidyl are not readily available. However, it is likely eliminated predominantly in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The mean elimination half life of trihexyphenidyl is 3.2 ± 0.3 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermia in high doses. Trihexyphenidyl causes agitation, confusion, and hallucinations due to its effects on the central nervous system. Untreated overdose may result in death, especially in children. Respiratory depression and cardiac arrest may be seen as premortal signs. Patients experiencing an overdose of trihexyphenidyl may experience dry mouth, anhidrosis, mydriasis, nausea, vomiting, tachycardia, hyperpyrexia, reduced gastrointestinal motility, urinary hesitancy or retention, rash, hyperthermia, confusion, restlessness, agitation, poor coordination, paranoia, psychosis, delirium, hallucinations, coma, respiratory failure, circulatory failure, and death. Patients should be treated with symptomatic and supportive care which may include airway maintenance and the use of physostigmine. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trihexyphenidyl is an antispasmodic drug used as an adjunct drug in the management of parkinsonism and as a treatment for extrapyramidal symptoms caused by drugs affecting the central nervous system (CNS).

Despite the fact that these drugs are sometimes used in combination to treat depression in Parkinson's disease3, the administration of bupropion with anti-Parkinson drugs may lead to central nervous system toxicity. Bupropion is considered a norepinephrine-dopamine reuptake inhibitor, is found to occupy the DAT dopamine transporter, and acts as a dopamine agonist. Additive effects of these dopaminergic drugs may produce excess dopaminergic activity. Agitation, restlessness, tremor, ataxia, gait disturbance, and dizziness are some examples of effects that may occur from concurrent administration. The severity of the interaction is moderate.

Question: Does Bupropion and Trihexyphenidyl interact? Information: •Drug A: Bupropion •Drug B: Trihexyphenidyl •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Bupropion is combined with Trihexyphenidyl. •Extended Description: Despite the fact that these drugs are sometimes used in combination to treat depression in Parkinson's disease3, the administration of bupropion with anti-Parkinson drugs may lead to central nervous system toxicity. Bupropion is considered a norepinephrine-dopamine reuptake inhibitor, is found to occupy the DAT dopamine transporter, and acts as a dopamine agonist. Additive effects of these dopaminergic drugs may produce excess dopaminergic activity. Agitation, restlessness, tremor, ataxia, gait disturbance, and dizziness are some examples of effects that may occur from concurrent administration. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tihexyphenidyl is indicated as an adjunct in the treatment of parkinsonism, an adjuvant in the treatment of parkinsonism with levodopa, and in the control of extrapyramidal disorders caused by central nervous system drugs. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trihexyphenidyl is an antimuscarinic indicated as an adjunct in the treatment of parkinsonism or as a treatment for drug-induced extrapyramidal symptoms. It has a long duration of action as it does not need to be given every day. It has a wide therapeutic window, with acute toxicity being non fatal in doses as high as 300 mg. Patients should have their iridocorneal angle examined before and intraocular pressure monitored during therapy. Patients should be counselled regarding the risk of anhidrosis and hyperthermia. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Trihexyphenidyl is a non-selective muscarinic acetylcholine receptor antagonist but binds with higher affinity to the M1 subtype. In vivo studies have shown that trihexyphenidyl demonstrates higher affinity for central muscarinic receptors located in the cerebral cortex and lower affinity for those located peripherally. Other studies suggest that trihexyphenidyl may modify nicotinic acetylcholine receptor neurotransmission, leading indirectly to enhanced dopamine release in the striatum. Although the anticholinergic has proven to be useful in the treatment of symptoms associated with Parkinson’s disease or other movement disorders, its mechanism of action has yet to be fully elucidated. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Trihexyphenidyl is absorbed from the gastrointestinal tract. Trihexyphenidyl reaches a C max of 7.2 ng/mL, with a T max of 1.3 hours, and an AUC of 201 ng*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Data regarding the extent of trihexyphenidyl protein binding in plasma are not readily available. Trihexyphenidyl is 36.13-41.92% bound to albumin under controlled conditions in a dialysis bag. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Data regarding the metabolism of trihexyphenidyl are not readily available. However, it is likely not heavily metabolized. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Data regarding the route of elimination of trihexyphenidyl are not readily available. However, it is likely eliminated predominantly in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The mean elimination half life of trihexyphenidyl is 3.2 ± 0.3 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermia in high doses. Trihexyphenidyl causes agitation, confusion, and hallucinations due to its effects on the central nervous system. Untreated overdose may result in death, especially in children. Respiratory depression and cardiac arrest may be seen as premortal signs. Patients experiencing an overdose of trihexyphenidyl may experience dry mouth, anhidrosis, mydriasis, nausea, vomiting, tachycardia, hyperpyrexia, reduced gastrointestinal motility, urinary hesitancy or retention, rash, hyperthermia, confusion, restlessness, agitation, poor coordination, paranoia, psychosis, delirium, hallucinations, coma, respiratory failure, circulatory failure, and death. Patients should be treated with symptomatic and supportive care which may include airway maintenance and the use of physostigmine. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trihexyphenidyl is an antispasmodic drug used as an adjunct drug in the management of parkinsonism and as a treatment for extrapyramidal symptoms caused by drugs affecting the central nervous system (CNS). Output: Despite the fact that these drugs are sometimes used in combination to treat depression in Parkinson's disease3, the administration of bupropion with anti-Parkinson drugs may lead to central nervous system toxicity. Bupropion is considered a norepinephrine-dopamine reuptake inhibitor, is found to occupy the DAT dopamine transporter, and acts as a dopamine agonist. Additive effects of these dopaminergic drugs may produce excess dopaminergic activity. Agitation, restlessness, tremor, ataxia, gait disturbance, and dizziness are some examples of effects that may occur from concurrent administration. The severity of the interaction is moderate.

Does Bupropion and Trimebutine interact?

•Drug A: Bupropion •Drug B: Trimebutine •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Trimebutine which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated for symptomatic treatment of irritable bowel syndrome (IBS) and treatment of postoperative paralytic ileus following abdominal surgery. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trimebutine is a spasmolytic agent that acts directly on smooth muscle to modulate gastric motility. It shows a "dual function" that stimulates or inhibits spontaneous contractions depending on the concentration and prior contractile activity in the preparation. Targeting ion conductance that regulates GI motility, trimebutine inhibits the inward calcium currents and calcium-dependent potassium currents in a concentration-dependent manner. At lower concentrations (1-10uM), trimebutine depolarizes the resting membrane potential without affecting the amplitude of contractions, which is thought to be mediated by inhibition of outward potassium currents. It is also shown to activate T-type Ca2+ channel and increase gastric emptying, intestinal and colonic contractility. At higher concentrations (100-300uM), reduced amplitude of spontaneous contractions and action potentials is thought to be mediated by inhibition of L-type Ca2+ channels and inward calcium current. Trimebutine mediates a local anesthetic action by acting as a weak agonist at mu opioid receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): At high concentrations, trimebutine is shown to inhibit the extracellular Ca2+ influx in the smooth muscle cells through voltage dependent L-type Ca2+ channels and further Ca2+ release from intracellular Ca2+ stores. Trimebutine is suggested to bind to the inactivated state of the calcium channel with high affinity. Reduced calcium influx attenuates membrane depolarization and decrease colon peristalsis. It also inhibits outward K+ currents in response to membrane depolarization of the GI smooth muscle cells at resting conditions through inhibition of delayed rectifier K+ channels and Ca2+ dependent K+ channels, which results in induced muscle contractions. Trimebutine binds to mu opioid receptors with more selectivity compared to delta or kappa opioid receptors but with lower affinity than their natural ligands. Its metabolites (N-monodesmethyl-trimebutine or nor-trimebutine), are also shown to bind to opoid receptors on brain membranes and myenteric synaptosomes. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The free base form or salt form of trimebutine are rapidly absorbed after oral administration, with the peak plasma concentration reached after 1 hour of ingestion. The time to reach peak plasma concentration following a single oral dose of 200mg trimebutine is 0.80 hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Trimebutine is most likely to be accumulated in the stomach and the intestinal walls in highest concentrations. The fetal transfer is reported to be low. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Protein binding is minimal with 5% in vivo and in vitro to serum albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Trimebutine undergoes extensive hepatic first-pass metabolism. Nortrimebutine, or N-monodesmethyltrimebutine, is the main metabolite that retains pharmacological activity on the colon. This metabolite can undergo second N-demethylation to form N-didesmethyltrimebutine. Other main urinary metabolites (2-amino, 2-methylamino or 2-dimethylamino-2-phenylbutan-1-ol) can be formed via hydrolysis of the ester bond of desmethylated metabolites or initial hydrolysis of the ester bond of trimebutine followed by sequential N-demethylation. Trimebutine is also prone to sulphate and/or glucuronic acid conjugation. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Renal elimination is predominant while excretion into feces is also observed (5-12%). About 94% of an oral dose of trimebutine is eliminated by the kidneys in the form of various metabolites and less than 2.4% of total ingested drug is recovered as unchanged parent drug in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half life is approximately 1 hour following a single oral dose of 2mg/kg, and 2.77 hours following a single oral dose 200 mg. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Common gastrointestinal adverse effects include dry mouth, foul taste, diarrhea, dyspepsia, epigastric pain, nausea and constipation. Some CNS effects include drowsiness, fatigue, dizziness, hot/cold sensations and headaches. In case of overdosage, gastric lavage is recommended. Oral LD50 in mouse and rats is >5000 mg/kg and 2500 mg/kg in rabbits, respectively. Trimebutine is not reported to display teratogenic, mutagenic or carcinogenic potential. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trimébutine Trimebutine Trimebutino •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trimebutine is a spasmolytic agent used for the symptomatic treatment of irritable bowel syndrome (IBS) and treatment of postoperative paralytic ileus following abdominal surgery.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Trimebutine interact? Information: •Drug A: Bupropion •Drug B: Trimebutine •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Trimebutine which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated for symptomatic treatment of irritable bowel syndrome (IBS) and treatment of postoperative paralytic ileus following abdominal surgery. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trimebutine is a spasmolytic agent that acts directly on smooth muscle to modulate gastric motility. It shows a "dual function" that stimulates or inhibits spontaneous contractions depending on the concentration and prior contractile activity in the preparation. Targeting ion conductance that regulates GI motility, trimebutine inhibits the inward calcium currents and calcium-dependent potassium currents in a concentration-dependent manner. At lower concentrations (1-10uM), trimebutine depolarizes the resting membrane potential without affecting the amplitude of contractions, which is thought to be mediated by inhibition of outward potassium currents. It is also shown to activate T-type Ca2+ channel and increase gastric emptying, intestinal and colonic contractility. At higher concentrations (100-300uM), reduced amplitude of spontaneous contractions and action potentials is thought to be mediated by inhibition of L-type Ca2+ channels and inward calcium current. Trimebutine mediates a local anesthetic action by acting as a weak agonist at mu opioid receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): At high concentrations, trimebutine is shown to inhibit the extracellular Ca2+ influx in the smooth muscle cells through voltage dependent L-type Ca2+ channels and further Ca2+ release from intracellular Ca2+ stores. Trimebutine is suggested to bind to the inactivated state of the calcium channel with high affinity. Reduced calcium influx attenuates membrane depolarization and decrease colon peristalsis. It also inhibits outward K+ currents in response to membrane depolarization of the GI smooth muscle cells at resting conditions through inhibition of delayed rectifier K+ channels and Ca2+ dependent K+ channels, which results in induced muscle contractions. Trimebutine binds to mu opioid receptors with more selectivity compared to delta or kappa opioid receptors but with lower affinity than their natural ligands. Its metabolites (N-monodesmethyl-trimebutine or nor-trimebutine), are also shown to bind to opoid receptors on brain membranes and myenteric synaptosomes. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The free base form or salt form of trimebutine are rapidly absorbed after oral administration, with the peak plasma concentration reached after 1 hour of ingestion. The time to reach peak plasma concentration following a single oral dose of 200mg trimebutine is 0.80 hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Trimebutine is most likely to be accumulated in the stomach and the intestinal walls in highest concentrations. The fetal transfer is reported to be low. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Protein binding is minimal with 5% in vivo and in vitro to serum albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Trimebutine undergoes extensive hepatic first-pass metabolism. Nortrimebutine, or N-monodesmethyltrimebutine, is the main metabolite that retains pharmacological activity on the colon. This metabolite can undergo second N-demethylation to form N-didesmethyltrimebutine. Other main urinary metabolites (2-amino, 2-methylamino or 2-dimethylamino-2-phenylbutan-1-ol) can be formed via hydrolysis of the ester bond of desmethylated metabolites or initial hydrolysis of the ester bond of trimebutine followed by sequential N-demethylation. Trimebutine is also prone to sulphate and/or glucuronic acid conjugation. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Renal elimination is predominant while excretion into feces is also observed (5-12%). About 94% of an oral dose of trimebutine is eliminated by the kidneys in the form of various metabolites and less than 2.4% of total ingested drug is recovered as unchanged parent drug in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half life is approximately 1 hour following a single oral dose of 2mg/kg, and 2.77 hours following a single oral dose 200 mg. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Common gastrointestinal adverse effects include dry mouth, foul taste, diarrhea, dyspepsia, epigastric pain, nausea and constipation. Some CNS effects include drowsiness, fatigue, dizziness, hot/cold sensations and headaches. In case of overdosage, gastric lavage is recommended. Oral LD50 in mouse and rats is >5000 mg/kg and 2500 mg/kg in rabbits, respectively. Trimebutine is not reported to display teratogenic, mutagenic or carcinogenic potential. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trimébutine Trimebutine Trimebutino •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trimebutine is a spasmolytic agent used for the symptomatic treatment of irritable bowel syndrome (IBS) and treatment of postoperative paralytic ileus following abdominal surgery. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Trimethobenzamide interact?

•Drug A: Bupropion •Drug B: Trimethobenzamide •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Trimethobenzamide is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of postoperative nausea and vomiting and for nausea associated with gastroenteritis. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trimethobenzamide is a novel antiemetic which prevents nausea and vomiting in humans. Its actions are unclear but most likely involves the chemoreceptor trigger zone (CTZ). In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine is inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of trimethobenzamide as determined in animals is obscure, but may involve the chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic impulses are conveyed to the vomiting center; direct impulses to the vomiting center apparently are not similarly inhibited. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The relative bioavailability of the capsule formulation compared to the solution is 100%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Between 30 – 50% of a single dose in humans is excreted unchanged in the urine within 48–72 hours. •Half-life (Drug A): 24 hours •Half-life (Drug B): The mean elimination half-life of trimethobenzamide is 7 to 9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral LD 50 in mice is 1600 mg/kg. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tigan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trimethobenzamide Trimethobenzamidum Trimetobenzamida •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trimethobenzamide is an antiemetic used to treat postoperative nausea and vomiting and nausea associated with gastroenteritis.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Trimethobenzamide interact? Information: •Drug A: Bupropion •Drug B: Trimethobenzamide •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Trimethobenzamide is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of postoperative nausea and vomiting and for nausea associated with gastroenteritis. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trimethobenzamide is a novel antiemetic which prevents nausea and vomiting in humans. Its actions are unclear but most likely involves the chemoreceptor trigger zone (CTZ). In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine is inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of trimethobenzamide as determined in animals is obscure, but may involve the chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic impulses are conveyed to the vomiting center; direct impulses to the vomiting center apparently are not similarly inhibited. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The relative bioavailability of the capsule formulation compared to the solution is 100%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Between 30 – 50% of a single dose in humans is excreted unchanged in the urine within 48–72 hours. •Half-life (Drug A): 24 hours •Half-life (Drug B): The mean elimination half-life of trimethobenzamide is 7 to 9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral LD 50 in mice is 1600 mg/kg. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Tigan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trimethobenzamide Trimethobenzamidum Trimetobenzamida •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trimethobenzamide is an antiemetic used to treat postoperative nausea and vomiting and nausea associated with gastroenteritis. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Trimethoprim interact?

•Drug A: Bupropion •Drug B: Trimethoprim •Severity: MINOR •Description: Trimethoprim may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): As a monotherapy, trimethoprim is indicated for the treatment of acute episodes of uncomplicated urinary tract infections caused by susceptible bacteria, including E. coli., K. pneumoniae, Enterobacter spp., P. mirabilis, and coagulase-negative Staphylococcus species. In various formulations in combination with sulfamethoxazole, trimethoprim is indicated for the following infections caused by bacteria with documented susceptibility: urinary tract infections, acute otitis media in pediatric patients (when clinically indicated), acute exacerbations of chronic bronchitis in adults, enteritis caused by susceptible Shigella, prophylaxis and treatment of Pneumocystis jiroveci pneumonia, and travelers' diarrhea caused by enterotoxigenic E. coli. Trimethoprim is available as an ophthalmic solution in combination with polymyxin B for the treatment of acute bacterial conjunctivitis, blepharitis, and blepharoconjunctivitis caused by susceptible bacteria. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trimethoprim exerts its antimicrobial effects by inhibiting an essential step in the synthesis of bacterial nucleic acids and proteins. It has shown activity against several species of gram-negative bacteria, as well as coagulase-negative Staphylococcus species. Resistance to trimethoprim may arise via a variety of mechanisms, including alterations to the bacterial cell wall, overproduction of dihydrofolate reductase, or production of resistant dihydrofolate reductase. Rarely, trimethoprim can precipitate the development of blood disorders (e.g. thrombocytopenia, leukopenia, etc.) which may be preceded by symptoms such as sore throat, fever, pallor, and or purpura - patients should be monitored closely for the development of these symptoms throught the course of therapy. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Trimethoprim is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Trimethoprim binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes. Trimethoprim is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal activity. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Steady-state concentrations are achieved after approximately 3 days of repeat administration. Average peak serum concentrations of approximately 1 µg/mL (C max ) are achieved within 1 to 4 hours (T max ) following the administration of a single 100mg dose. Trimethoprim appears to follow first-order pharmacokinetics, as a single 200mg dose results in serum concentrations approximately double that of a 100mg dose. The steady-state AUC of orally administered trimethoprim is approximately 30 mg/L·h. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Trimethoprim is extensively distributed into various tissues following oral administration. It distributes well into sputum, middle ear fluid, and bronchial secretions. Trimethoprim distributes efficiently into vaginal fluids, with observed concentrations approximately 1.6-fold higher than those seen in the serum. It may pass the placental barrier and into breast milk. Trimethoprim is also sufficiently excreted in the feces to markedly reduce and/or eliminate trimethoprim-susceptible fecal flora. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Trimethoprim is 44% bound to plasma proteins, though the specific proteins to which it binds have not been elucidated. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Trimethoprim undergoes oxidative metabolism to a number of metabolites, the most abundant of which are the demethylated 3'- and 4'- metabolites, accounting for approximately 65% and 25% of the total metabolite formation, respectively. Minor products include N-oxide metabolites (<5%) and benzylic metabolites in even smaller quantities. The parent drug is considered to be the therapeutically active form. The majority of trimethoprim biotransformation appears to involve CYP2C9 and CYP3A4 enzymes, with CYP1A2 contributing to a lesser extent. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 10-20% of an ingested trimethoprim dose is metabolized, primarily in the liver, while a large portion of the remainder is excreted unchanged in the urine. Following oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of which is unchanged parent drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): Trimethoprim half-life ranges from 8-10 hours, but may be prolonged in patients with renal dysfunction. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following oral administration, the renal clearance of trimethoprim has been variably reported between 51.7 - 91.3 mL/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 in mice and rats is 2764 mg/kg and >5300 mg/kg, respectively. Prescribing information for trimethoprim states that signs of overdose may be evident following ingestion of doses >1 gram, and may include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression. Treatment should consist of general supportive measures and gastric lavage, if applicable. Urinary acidification may increase renal elimination of trimethoprim. Hemodialysis is only moderately effective in eliminating trimethoprim and peritoneal dialysis is of no benefit. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Bactrim, Polytrim, Primsol, Septra, Sulfatrim •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trimethoprim Triméthoprime Trimethoprimum Trimetoprima •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trimethoprim is an antifolate antibiotic often used in combination with sulfamethoxazole to treat a number of infections, including those of the urinary tract, respiratory tract, and gastrointestinal tract.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Trimethoprim interact? Information: •Drug A: Bupropion •Drug B: Trimethoprim •Severity: MINOR •Description: Trimethoprim may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): As a monotherapy, trimethoprim is indicated for the treatment of acute episodes of uncomplicated urinary tract infections caused by susceptible bacteria, including E. coli., K. pneumoniae, Enterobacter spp., P. mirabilis, and coagulase-negative Staphylococcus species. In various formulations in combination with sulfamethoxazole, trimethoprim is indicated for the following infections caused by bacteria with documented susceptibility: urinary tract infections, acute otitis media in pediatric patients (when clinically indicated), acute exacerbations of chronic bronchitis in adults, enteritis caused by susceptible Shigella, prophylaxis and treatment of Pneumocystis jiroveci pneumonia, and travelers' diarrhea caused by enterotoxigenic E. coli. Trimethoprim is available as an ophthalmic solution in combination with polymyxin B for the treatment of acute bacterial conjunctivitis, blepharitis, and blepharoconjunctivitis caused by susceptible bacteria. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trimethoprim exerts its antimicrobial effects by inhibiting an essential step in the synthesis of bacterial nucleic acids and proteins. It has shown activity against several species of gram-negative bacteria, as well as coagulase-negative Staphylococcus species. Resistance to trimethoprim may arise via a variety of mechanisms, including alterations to the bacterial cell wall, overproduction of dihydrofolate reductase, or production of resistant dihydrofolate reductase. Rarely, trimethoprim can precipitate the development of blood disorders (e.g. thrombocytopenia, leukopenia, etc.) which may be preceded by symptoms such as sore throat, fever, pallor, and or purpura - patients should be monitored closely for the development of these symptoms throught the course of therapy. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Trimethoprim is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Trimethoprim binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes. Trimethoprim is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal activity. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Steady-state concentrations are achieved after approximately 3 days of repeat administration. Average peak serum concentrations of approximately 1 µg/mL (C max ) are achieved within 1 to 4 hours (T max ) following the administration of a single 100mg dose. Trimethoprim appears to follow first-order pharmacokinetics, as a single 200mg dose results in serum concentrations approximately double that of a 100mg dose. The steady-state AUC of orally administered trimethoprim is approximately 30 mg/L·h. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Trimethoprim is extensively distributed into various tissues following oral administration. It distributes well into sputum, middle ear fluid, and bronchial secretions. Trimethoprim distributes efficiently into vaginal fluids, with observed concentrations approximately 1.6-fold higher than those seen in the serum. It may pass the placental barrier and into breast milk. Trimethoprim is also sufficiently excreted in the feces to markedly reduce and/or eliminate trimethoprim-susceptible fecal flora. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Trimethoprim is 44% bound to plasma proteins, though the specific proteins to which it binds have not been elucidated. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Trimethoprim undergoes oxidative metabolism to a number of metabolites, the most abundant of which are the demethylated 3'- and 4'- metabolites, accounting for approximately 65% and 25% of the total metabolite formation, respectively. Minor products include N-oxide metabolites (<5%) and benzylic metabolites in even smaller quantities. The parent drug is considered to be the therapeutically active form. The majority of trimethoprim biotransformation appears to involve CYP2C9 and CYP3A4 enzymes, with CYP1A2 contributing to a lesser extent. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 10-20% of an ingested trimethoprim dose is metabolized, primarily in the liver, while a large portion of the remainder is excreted unchanged in the urine. Following oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of which is unchanged parent drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): Trimethoprim half-life ranges from 8-10 hours, but may be prolonged in patients with renal dysfunction. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following oral administration, the renal clearance of trimethoprim has been variably reported between 51.7 - 91.3 mL/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 in mice and rats is 2764 mg/kg and >5300 mg/kg, respectively. Prescribing information for trimethoprim states that signs of overdose may be evident following ingestion of doses >1 gram, and may include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression. Treatment should consist of general supportive measures and gastric lavage, if applicable. Urinary acidification may increase renal elimination of trimethoprim. Hemodialysis is only moderately effective in eliminating trimethoprim and peritoneal dialysis is of no benefit. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Bactrim, Polytrim, Primsol, Septra, Sulfatrim •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trimethoprim Triméthoprime Trimethoprimum Trimetoprima •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trimethoprim is an antifolate antibiotic often used in combination with sulfamethoxazole to treat a number of infections, including those of the urinary tract, respiratory tract, and gastrointestinal tract. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Trimetrexate interact?

•Drug A: Bupropion •Drug B: Trimetrexate •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Trimetrexate which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For use, with concurrent leucovorin administration (leucovorin protection), as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Also used to treat several types of cancer including colon cancer. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trimetrexate, a non-classical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase (DHFR). During DNA synthesis and cellular reproduction, folic acid is reduced to tetrahydrofolic acid by the enzyme folic acid reductase. By interfering with the reduction of folic acid, trimetrexate interferes with tissue cell reproduction. Generally, the most sensitive cells to the antimetabolite effect of trimetrexate are those cells which are most actively proliferating such as malignant cells, dermal epithelium, buccal and intestinal mucosa, bone marrow, fetal cells, and cells of the urinary bladder. Because the proliferation of cells in malignant tissues is greater than in most normal tissues, trimetrexate may impair the growth of the malignant tissues without causing irreversible damage to normal tissues. Due to very serious and potentially life-threatening side-effects of this drug, leucovorin must be co-administered for at least 72 hours after the last dose. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of p.r.n. biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 20 ± 8 L/m2 36.9 ± 6 L/m2 [cancer patients] •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 95% (over the concentration range of 18.75 to 1000 ng/mL) •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Ten to 30% of the administered dose is excreted unchanged in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): 11 to 20 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 38 +/- 15 mL/min/m2 [patients with acquired immunodeficiency syndrome (AIDS) who had Pneumocystis carinii pneumonia (4 patients) or toxoplasmosis (2 patients). Trimetrexate was administered intravenously as a bolus injection at a dose of 30 mg/m2/day along with leucovorin 20 mg/m2 every 6 hours for 21 days] 53 +/- 41 mL/min/m2 [Cancer patients with advanced solid tumors using various dosage regimensreceiving a single-dose administration of 10 to 130 mg/m2] 30 +/- 8 mL/min/m2 [Cancer patients with advanced solid tumors using various dosage regimensafter a five-day infusion] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The LD 50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m ). Myelosuppression is a dose-limiting toxic effect. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Neutrexin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trimetrexate is a folate antagonist used for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients as an alternative therapy in combination with leucovorin.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Trimetrexate interact? Information: •Drug A: Bupropion •Drug B: Trimetrexate •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Trimetrexate which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For use, with concurrent leucovorin administration (leucovorin protection), as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Also used to treat several types of cancer including colon cancer. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trimetrexate, a non-classical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase (DHFR). During DNA synthesis and cellular reproduction, folic acid is reduced to tetrahydrofolic acid by the enzyme folic acid reductase. By interfering with the reduction of folic acid, trimetrexate interferes with tissue cell reproduction. Generally, the most sensitive cells to the antimetabolite effect of trimetrexate are those cells which are most actively proliferating such as malignant cells, dermal epithelium, buccal and intestinal mucosa, bone marrow, fetal cells, and cells of the urinary bladder. Because the proliferation of cells in malignant tissues is greater than in most normal tissues, trimetrexate may impair the growth of the malignant tissues without causing irreversible damage to normal tissues. Due to very serious and potentially life-threatening side-effects of this drug, leucovorin must be co-administered for at least 72 hours after the last dose. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of p.r.n. biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 20 ± 8 L/m2 36.9 ± 6 L/m2 [cancer patients] •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 95% (over the concentration range of 18.75 to 1000 ng/mL) •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Ten to 30% of the administered dose is excreted unchanged in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): 11 to 20 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 38 +/- 15 mL/min/m2 [patients with acquired immunodeficiency syndrome (AIDS) who had Pneumocystis carinii pneumonia (4 patients) or toxoplasmosis (2 patients). Trimetrexate was administered intravenously as a bolus injection at a dose of 30 mg/m2/day along with leucovorin 20 mg/m2 every 6 hours for 21 days] 53 +/- 41 mL/min/m2 [Cancer patients with advanced solid tumors using various dosage regimensreceiving a single-dose administration of 10 to 130 mg/m2] 30 +/- 8 mL/min/m2 [Cancer patients with advanced solid tumors using various dosage regimensafter a five-day infusion] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The LD 50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m ). Myelosuppression is a dose-limiting toxic effect. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Neutrexin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trimetrexate is a folate antagonist used for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients as an alternative therapy in combination with leucovorin. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Trimipramine interact?

•Drug A: Bupropion •Drug B: Trimipramine •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Trimipramine. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of depression and depression accompanied by anxiety, agitation or sleep disturbance •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trimipramine is a tricyclic antidepressant. It was thought that tricyclic antidepressants work by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: a1 and b1 receptors are sensitized, a2 receptors are desensitised (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-pain opioid systems in the CNS via an indirect serotonergic route. They are also effective in migraine prophylaxis, but not in abortion of acute migraine attack. The mechanism of their anti-migraine action is also thought to be serotonergic. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Trimipramine's mechanism of action differs from other tricyclic antidepressants. Trimipramine acts by decreasing the reuptake of norepinephrine and serotonin (5-HT). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapid absorption •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 93%-96% (to plasma proteins) •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 11-18 hrs •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Side effects include agitation, coma, confusion, convulsions, dilated pupils, disturbed concentration, drowsiness, hallucinations, high fever, irregular heart rate, low body temperature, muscle rigidity, overactive reflexes, severely low blood pressure, stupor, vomiting •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trimeprimina Trimeprimine Trimeproprimine Trimipramina Trimipramine Trimipraminum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trimipramine is a tricyclic antidepressant used to treat depression.

Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Question: Does Bupropion and Trimipramine interact? Information: •Drug A: Bupropion •Drug B: Trimipramine •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Trimipramine. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of depression and depression accompanied by anxiety, agitation or sleep disturbance •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Trimipramine is a tricyclic antidepressant. It was thought that tricyclic antidepressants work by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: a1 and b1 receptors are sensitized, a2 receptors are desensitised (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-pain opioid systems in the CNS via an indirect serotonergic route. They are also effective in migraine prophylaxis, but not in abortion of acute migraine attack. The mechanism of their anti-migraine action is also thought to be serotonergic. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Trimipramine's mechanism of action differs from other tricyclic antidepressants. Trimipramine acts by decreasing the reuptake of norepinephrine and serotonin (5-HT). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapid absorption •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 93%-96% (to plasma proteins) •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 11-18 hrs •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Side effects include agitation, coma, confusion, convulsions, dilated pupils, disturbed concentration, drowsiness, hallucinations, high fever, irregular heart rate, low body temperature, muscle rigidity, overactive reflexes, severely low blood pressure, stupor, vomiting •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trimeprimina Trimeprimine Trimeproprimine Trimipramina Trimipramine Trimipraminum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Trimipramine is a tricyclic antidepressant used to treat depression. Output: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Does Bupropion and Triprolidine interact?

•Drug A: Bupropion •Drug B: Triprolidine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Triprolidine is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the symptomatic relief of seasonal or perennial allergic rhinitis or nonallergic rhinitis; allergic conjunctivitis; and mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Also used in combination with other agents for the symptomatic relief of symptoms associated with the common cold. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H1-receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Triprolidine, is a histamine H1 antagonist that competes with histamine for the normal H1-receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. Triprolidine has anticholinergic and sedative effects. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Triprolidine binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed in the intestinal tract. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 4 to 6 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include drowsiness, weakness, inco-ordination, difficulty with micturition, respiratory depression, hypotension, agitation, irritability, convulsions, hypertension, palpitation and tachycardia. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Covan, Histex Ac, Histex Pd Reformulated Mar 2014, Histex Syrup, Pseudodine C, Triacin-C, Vanaclear •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tripolidina Triprolidin Triprolidina Triprolidine Triprolidinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Triprolidine is a sedating antihistamine combined with pseudoephedrine and guaifenesin in various types of cold and allergy medications to relieve allergy symptoms, hay fever and common cold symptoms, and to aid in sleep.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Triprolidine interact? Information: •Drug A: Bupropion •Drug B: Triprolidine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Triprolidine is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the symptomatic relief of seasonal or perennial allergic rhinitis or nonallergic rhinitis; allergic conjunctivitis; and mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Also used in combination with other agents for the symptomatic relief of symptoms associated with the common cold. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H1-receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Triprolidine, is a histamine H1 antagonist that competes with histamine for the normal H1-receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. Triprolidine has anticholinergic and sedative effects. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Triprolidine binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed in the intestinal tract. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): 4 to 6 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include drowsiness, weakness, inco-ordination, difficulty with micturition, respiratory depression, hypotension, agitation, irritability, convulsions, hypertension, palpitation and tachycardia. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Covan, Histex Ac, Histex Pd Reformulated Mar 2014, Histex Syrup, Pseudodine C, Triacin-C, Vanaclear •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tripolidina Triprolidin Triprolidina Triprolidine Triprolidinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Triprolidine is a sedating antihistamine combined with pseudoephedrine and guaifenesin in various types of cold and allergy medications to relieve allergy symptoms, hay fever and common cold symptoms, and to aid in sleep. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Tropisetron interact?

•Drug A: Bupropion •Drug B: Tropisetron •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Bupropion is combined with Tropisetron. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the prevention of nausea and vomiting induced by cytotoxic therapy and postoperative. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tropisetron competitively binds to and blocks the action of serotonin at 5HT3 receptors peripherally on vagus nerve terminals located in the gastrointestinal (GI) tract as well as centrally in the chemoreceptor trigger zone (CTZ) of the area postrema of the central nervous system (CNS). This results in the suppression of chemotherapy- and radiotherapy-induced nausea and vomiting. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The absorption of tropisetron from the gastrointestinal tract is rapid (mean half-life of about 20 minutes) and nearly complete (more than 95%). Due to first-pass metabolism in the liver, the absolute bioavailability of a 5 mg oral dose is 60%. The peak plasma concentration is attained within three hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 400-600 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 71% bound to plasma protein in a non-specific manner. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The metabolism of tropisetron occurs by hydroxylation at the 5, 6 or 7 positions of its indole ring, followed by a conjugation reaction to the glucuronide or sulphate with excretion in the urine or bile (urine to faeces ratio 5:1). The metabolites have a greatly reduced potency for the 5-HT3 receptor and do not contribute to the pharmacological action of the drug. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 8% of tropisetron is excreted in the urine as unchanged drug, 70% as metabolites; 15% is excreted in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): 5.7 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): 1800 ml/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD50: 265 mg/kg (Rat, oral). •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tropisetron is a 5HT-3 receptor antagonist used as an antiemetic in the treatment of chemotherapy-induced nausea and vomiting.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Tropisetron interact? Information: •Drug A: Bupropion •Drug B: Tropisetron •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Bupropion is combined with Tropisetron. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the prevention of nausea and vomiting induced by cytotoxic therapy and postoperative. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Tropisetron competitively binds to and blocks the action of serotonin at 5HT3 receptors peripherally on vagus nerve terminals located in the gastrointestinal (GI) tract as well as centrally in the chemoreceptor trigger zone (CTZ) of the area postrema of the central nervous system (CNS). This results in the suppression of chemotherapy- and radiotherapy-induced nausea and vomiting. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The absorption of tropisetron from the gastrointestinal tract is rapid (mean half-life of about 20 minutes) and nearly complete (more than 95%). Due to first-pass metabolism in the liver, the absolute bioavailability of a 5 mg oral dose is 60%. The peak plasma concentration is attained within three hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 400-600 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 71% bound to plasma protein in a non-specific manner. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The metabolism of tropisetron occurs by hydroxylation at the 5, 6 or 7 positions of its indole ring, followed by a conjugation reaction to the glucuronide or sulphate with excretion in the urine or bile (urine to faeces ratio 5:1). The metabolites have a greatly reduced potency for the 5-HT3 receptor and do not contribute to the pharmacological action of the drug. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 8% of tropisetron is excreted in the urine as unchanged drug, 70% as metabolites; 15% is excreted in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): 5.7 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): 1800 ml/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD50: 265 mg/kg (Rat, oral). •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tropisetron is a 5HT-3 receptor antagonist used as an antiemetic in the treatment of chemotherapy-induced nausea and vomiting. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Tryptophan interact?

•Drug A: Bupropion •Drug B: Tryptophan •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Tryptophan is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tryptophan may be useful in increasing serotonin production, promoting healthy sleep, managing depression by enhancing mental and emotional well-being, managing pain tolerance, and managing weight. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tryptophan is critical for the production of the body's proteins, enzymes and muscle tissue. It is also essential for the production of niacin, the synthesis of the neurotransmitter serotonin and melatonin. Tryptophan supplements can be used as natural relaxants to help relieve insomnia. Tryptophan can also reduce anxiety and depression and has been shown to reduce the intensity of migraine headaches. Other promising indications include the relief of chronic pain, reduction of impulsivity or mania and the treatment of obsessive or compulsive disorders. Tryptophan also appears to help the immune system and can reduce the risk of cardiac spasms. Tryptophan deficiencies may lead to coronary artery spasms. Tryptophan is used as an essential nutrient in infant formulas and intravenous feeding. Tryptophan is marketed as a prescription drug (Tryptan) for those who do not seem to respond well to conventional antidepressants. It may also be used to treat those afflicted with seasonal affective disorder (a winter-onset depression). Tryptopan serves as the precursor for the synthesis of serotonin (5-hydroxytryptamine, 5-HT) and melatonin (N-acetyl-5-methoxytryptamine). •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): A number of important side reactions occur during the catabolism of tryptophan on the pathway to acetoacetate. The first enzyme of the catabolic pathway is an iron porphyrin oxygenase that opens the indole ring. The latter enzyme is highly inducible, its concentration rising almost 10-fold on a diet high in tryptophan. Kynurenine is the first key branch point intermediate in the pathway. Kynurenine undergoes deamniation in a standard transamination reaction yielding kynurenic acid. Kynurenic acid and metabolites have been shown to act as antiexcitotoxics and anticonvulsives. A second side branch reaction produces anthranilic acid plus alanine. Another equivalent of alanine is produced further along the main catabolic pathway, and it is the production of these alanine residues that allows tryptophan to be classified among the glucogenic and ketogenic amino acids. The second important branch point converts kynurenine into 2-amino-3-carboxymuconic semialdehyde, which has two fates. The main flow of carbon elements from this intermediate is to glutarate. An important side reaction in liver is a transamination and several rearrangements to produce limited amounts of nicotinic acid, which leads to production of a small amount of NAD and NADP. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral rat LD 50: > 16 gm/kg. Investigated as a tumorigen, mutagen, reproductive effector. Symptoms of overdose include agitation, confusion, diarrhea, fever, overactive reflexes, poor coordination, restlessness, shivering, sweating, talking or acting with excitement you cannot control, trembling or shaking, twitching, and vomiting. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Aminosyn II 7 %, Sulfite-free, Aminosyn-PF 7%, Clinimix 2.75/5, Clinimix E 2.75/5, Clinisol 15, Freamine 6.9, Freamine III 10, Hepatamine 8, Nephramine, Olimel, Periolimel, Plenamine, Premasol, Primene, Procalamine 3, Prosol, Travasol 10, Trophamine 10 %, Tryptan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-Tryptophan L-Tryptophan Triptofano Tryptophan Tryptophane Tryptophanum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tryptophan is an amino acid commonly found as a component of total parenteral nutrition.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Tryptophan interact? Information: •Drug A: Bupropion •Drug B: Tryptophan •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Tryptophan is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Tryptophan may be useful in increasing serotonin production, promoting healthy sleep, managing depression by enhancing mental and emotional well-being, managing pain tolerance, and managing weight. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Tryptophan is critical for the production of the body's proteins, enzymes and muscle tissue. It is also essential for the production of niacin, the synthesis of the neurotransmitter serotonin and melatonin. Tryptophan supplements can be used as natural relaxants to help relieve insomnia. Tryptophan can also reduce anxiety and depression and has been shown to reduce the intensity of migraine headaches. Other promising indications include the relief of chronic pain, reduction of impulsivity or mania and the treatment of obsessive or compulsive disorders. Tryptophan also appears to help the immune system and can reduce the risk of cardiac spasms. Tryptophan deficiencies may lead to coronary artery spasms. Tryptophan is used as an essential nutrient in infant formulas and intravenous feeding. Tryptophan is marketed as a prescription drug (Tryptan) for those who do not seem to respond well to conventional antidepressants. It may also be used to treat those afflicted with seasonal affective disorder (a winter-onset depression). Tryptopan serves as the precursor for the synthesis of serotonin (5-hydroxytryptamine, 5-HT) and melatonin (N-acetyl-5-methoxytryptamine). •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): A number of important side reactions occur during the catabolism of tryptophan on the pathway to acetoacetate. The first enzyme of the catabolic pathway is an iron porphyrin oxygenase that opens the indole ring. The latter enzyme is highly inducible, its concentration rising almost 10-fold on a diet high in tryptophan. Kynurenine is the first key branch point intermediate in the pathway. Kynurenine undergoes deamniation in a standard transamination reaction yielding kynurenic acid. Kynurenic acid and metabolites have been shown to act as antiexcitotoxics and anticonvulsives. A second side branch reaction produces anthranilic acid plus alanine. Another equivalent of alanine is produced further along the main catabolic pathway, and it is the production of these alanine residues that allows tryptophan to be classified among the glucogenic and ketogenic amino acids. The second important branch point converts kynurenine into 2-amino-3-carboxymuconic semialdehyde, which has two fates. The main flow of carbon elements from this intermediate is to glutarate. An important side reaction in liver is a transamination and several rearrangements to produce limited amounts of nicotinic acid, which leads to production of a small amount of NAD and NADP. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral rat LD 50: > 16 gm/kg. Investigated as a tumorigen, mutagen, reproductive effector. Symptoms of overdose include agitation, confusion, diarrhea, fever, overactive reflexes, poor coordination, restlessness, shivering, sweating, talking or acting with excitement you cannot control, trembling or shaking, twitching, and vomiting. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Aminosyn II 7 %, Sulfite-free, Aminosyn-PF 7%, Clinimix 2.75/5, Clinimix E 2.75/5, Clinisol 15, Freamine 6.9, Freamine III 10, Hepatamine 8, Nephramine, Olimel, Periolimel, Plenamine, Premasol, Primene, Procalamine 3, Prosol, Travasol 10, Trophamine 10 %, Tryptan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-Tryptophan L-Tryptophan Triptofano Tryptophan Tryptophane Tryptophanum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Tryptophan is an amino acid commonly found as a component of total parenteral nutrition. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Umeclidinium interact?

•Drug A: Bupropion •Drug B: Umeclidinium •Severity: MAJOR •Description: The metabolism of Umeclidinium can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Umeclidinium is approved by the FDA and Health Canada for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Additionally, umeclidinium also exists as combination products with vilanterol or vilanterol and fluticasone furoate. Both products were indicated for the maintenance treatment of COPD, but only the umeclidinium/ vilanterol / fluticasone furoate product was approved for the maintenance treatment of asthma in patients aged 18 years and older. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled, crossover trial in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent. In humans, the M3 receptor has been heavily implicated in the pathophysiology of asthma and COPD. Once the M3 receptor is activated, the phospholipase C would phosphorylate downstream targets, forming inositol 1,4,5-trisphosphate and eventually releasing intracellular Ca. Increase in intracellular Ca results in muscle contraction, thus worsening COPD and asthma-related bronchoconstriction. Additionally, M3 receptor activation also regulates pathways involving CD38, cyclic ADP ribose (cADPR), and ryanodine receptor channels, all of which control the intracellular Ca homeostasis that will lead to muscle contraction. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Umeclidinium is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, C max occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 14 days with 1.8-fold accumulation. The absolute bioavailability of inhaled umeclidinium was on average 13% of the dose, with negligible contribution from oral absorption. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): In vitro plasma protein binding in human plasma was on average 89%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption. •Half-life (Drug A): 24 hours •Half-life (Drug B): The effective half-life after once-daily inhaled dosing is 11 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Plasma clearance following intravenous administration was 151 L/hour. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): In separate embryofetal developmental studies, pregnant rats and rabbits received umeclidinium during the period of organogenesis at doses up to approximately 50 and 200 times the maximum recommended human daily inhaled dose (MRHDID), respectively (on an AUC basis at maternal inhalation doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits). No evidence of teratogenic effects was observed in either species. In a perinatal and postnatal developmental study in rats, dams received umeclidinium during late gestation and lactation periods with no evidence of effects on offspring development at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day). Based on available data, no adjustment of the dosage of umeclidinium in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of umeclidinium included 810 subjects aged 65 years and older, and, of those, 183 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively). Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay. No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and at inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC basis). No human overdosage data has been reported with umeclidinium High doses of umeclidinium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg of umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD. Treatment of overdosage consists of discontinuation of INCRUSE ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. In clinical trials, the most common adverse effects of umeclidinium were nasopharyngitis, upper respiratory tract infection, cough, and arthralgia. Atrial fibrillation occurred in <1% of patients, but was more common among patients treated with umeclidinium than in those treated with placebo. Anticholinergics like umeclidinium should be used with caution in patients with narrow-angle glaucoma and in those with prostatic hyperplasia or bladder-neck obstruction. Inhaled medications can cause paradoxical bronchospasm, which can be fatal. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Anoro, Anoro Ellipta, Incruse Ellipta, Trelegy Ellipta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Umeclidinium •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Umeclidinium is a long-acting muscarinic antagonist used as a long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).

The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Umeclidinium interact? Information: •Drug A: Bupropion •Drug B: Umeclidinium •Severity: MAJOR •Description: The metabolism of Umeclidinium can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Umeclidinium is approved by the FDA and Health Canada for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Additionally, umeclidinium also exists as combination products with vilanterol or vilanterol and fluticasone furoate. Both products were indicated for the maintenance treatment of COPD, but only the umeclidinium/ vilanterol / fluticasone furoate product was approved for the maintenance treatment of asthma in patients aged 18 years and older. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled, crossover trial in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent. In humans, the M3 receptor has been heavily implicated in the pathophysiology of asthma and COPD. Once the M3 receptor is activated, the phospholipase C would phosphorylate downstream targets, forming inositol 1,4,5-trisphosphate and eventually releasing intracellular Ca. Increase in intracellular Ca results in muscle contraction, thus worsening COPD and asthma-related bronchoconstriction. Additionally, M3 receptor activation also regulates pathways involving CD38, cyclic ADP ribose (cADPR), and ryanodine receptor channels, all of which control the intracellular Ca homeostasis that will lead to muscle contraction. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Umeclidinium is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, C max occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 14 days with 1.8-fold accumulation. The absolute bioavailability of inhaled umeclidinium was on average 13% of the dose, with negligible contribution from oral absorption. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): In vitro plasma protein binding in human plasma was on average 89%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption. •Half-life (Drug A): 24 hours •Half-life (Drug B): The effective half-life after once-daily inhaled dosing is 11 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Plasma clearance following intravenous administration was 151 L/hour. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): In separate embryofetal developmental studies, pregnant rats and rabbits received umeclidinium during the period of organogenesis at doses up to approximately 50 and 200 times the maximum recommended human daily inhaled dose (MRHDID), respectively (on an AUC basis at maternal inhalation doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits). No evidence of teratogenic effects was observed in either species. In a perinatal and postnatal developmental study in rats, dams received umeclidinium during late gestation and lactation periods with no evidence of effects on offspring development at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day). Based on available data, no adjustment of the dosage of umeclidinium in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of umeclidinium included 810 subjects aged 65 years and older, and, of those, 183 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively). Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay. No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and at inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC basis). No human overdosage data has been reported with umeclidinium High doses of umeclidinium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg of umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD. Treatment of overdosage consists of discontinuation of INCRUSE ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. In clinical trials, the most common adverse effects of umeclidinium were nasopharyngitis, upper respiratory tract infection, cough, and arthralgia. Atrial fibrillation occurred in <1% of patients, but was more common among patients treated with umeclidinium than in those treated with placebo. Anticholinergics like umeclidinium should be used with caution in patients with narrow-angle glaucoma and in those with prostatic hyperplasia or bladder-neck obstruction. Inhaled medications can cause paradoxical bronchospasm, which can be fatal. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Anoro, Anoro Ellipta, Incruse Ellipta, Trelegy Ellipta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Umeclidinium •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Umeclidinium is a long-acting muscarinic antagonist used as a long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). Output: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Vadadustat interact?

•Drug A: Bupropion •Drug B: Vadadustat •Severity: MINOR •Description: The serum concentration of Bupropion can be decreased when it is combined with Vadadustat. •Extended Description: Vadadustat is a mild inducer of CYP2B6. Therefore, the co-administration of vadadustat with sensitive substrates of CYP2B6 may alter their pharmacokinetics and decrease their concentration. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vadadustat is indicated for the treatment of symptomatic anemia associated with chronic kidney disease (CKD) in adults on chronic maintenance dialysis. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): The use of vadadustat was compared to darbepoetin alfa for the treatment of anemia in adult patients with dialysis-dependent chronic kidney disease. Vadadustat was non-inferior to darbepoetin alfa and met the primary hemoglobin level endpoint. In healthy subjects given 600 mg to 1200 mg of vadadustat, the use of this drug was not associated with clinically significant QTc prolongation. Compared to darbepoetin alfa, patients with dialysis-dependent chronic kidney disease treated with vadadustat have similar risks for death, myocardial infarction and stroke. The use of vadadustat may also lead to the development of thromboembolic events, hepatic impairment, hepatotoxicity, convulsions, as well as an increase in blood pressure. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Hypoxia-inducible factors (HIFs) are transcription factors responsible for cellular survival under hypoxic conditions. They regulate a number of processes including angiogenesis, cell growth and differentiation, various metabolic processes, and erythropoiesis. Under normoxic conditions, HIFs are degraded via hydroxylation by prolyl-hydroxylase dioxygenases. Vadadustat is an inhibitor of HIF-prolyl-hydroxylases (HIF-PHI), that facilitates increased HIF activity in the absence of hypoxic conditions. The increased levels of HIF prompted by vadadustat stimulate endogenous erythropoietin production, increasing iron mobilization and contributing to the gradual rise of hemoglobin levels and the correction of iron metabolism. In patients with anemia of chronic kidney disease, in whom normal erythropoiesis is dysfunctional, this leads to the correction of anemia. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Following single and repeated doses, vadadustat is rapidly absorbed. The T max of vadadustat ranges between 2 and 3 hr. No significant accumulation was detected in healthy subjects given repeated doses of vadadustat. Compared to fasted conditions, the administration of a 450 mg vadadustat tablet with a standard high-fat meal decreased the C max and AUC by 27% and 6%, respectively. Vadadustat may be taken with or without food. The mean blood-to-plasma ratio of vadadustat went from 0.50 to 0.55, suggesting that the sequestration of vadadustat into red blood cells is minimal. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution of vadadustat in patients with chronic kidney disease is 11.6 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The protein binding of vadadustat is greater than or equal to 99.5% in human plasma. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vadadustat is mainly metabolized by UDP-glucuronosyltransferase (UGT) enzymes, forming O-glucuronide conjugates via direct glucuronidation. The metabolism of vadadustat via cytochrome P450s (CYPs) is minimal. The major metabolite of vadadustat is vadadustat-O-glucuronide, which has 15% of the AUC of plasma radioactivity, and it is catalyzed by multiple UGT enzymes, including UGT1A1, UGT1A7, UGT1A8 and UGT1A9. Vadadustat acyl glucuronide is a minor metabolite with 0.047% of the total radioactivity in plasma. None of the vadadustat metabolites are active. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): In healthy subjects given a single dose of 650 mg of radiolabelled vadadustat, 85.9% of the dose was recovered, with 58.9% appearing in urine and 26.9% in feces. Small amounts of the unchanged form of vadadustat are excreted in urine and feces (<1% and 9%, respectively). •Half-life (Drug A): 24 hours •Half-life (Drug B): In patients with dialysis-dependent chronic kidney disease, the half-life of vadadustat was 9.2 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In healthy subjects given a single dose of 300 mg of vadadustat, the apparent total body clearance ranged from 1.7 L/h to 1.9 L/h. In patients with chronic kidney disease, the clearance of vadadustat is 0.8 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): An overdose of vadadustat may lead to extensions of the pharmacologic effects, such as increased hemoglobin levels and secondary polycythemia. In case of overdose, patients should be managed with clinically appropriate measures, such as dose reduction or treatment discontinuation. Patients should be carefully monitored and treated as clinically indicated. Approximately 16% of the vadadustat dose is removed by dialysis. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Vafseo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Vadadustat •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vadadustat is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor used to treat symptomatic anemia associated with chronic kidney disease in adults on chronic maintenance dialysis.

Vadadustat is a mild inducer of CYP2B6. Therefore, the co-administration of vadadustat with sensitive substrates of CYP2B6 may alter their pharmacokinetics and decrease their concentration. The severity of the interaction is minor.

Question: Does Bupropion and Vadadustat interact? Information: •Drug A: Bupropion •Drug B: Vadadustat •Severity: MINOR •Description: The serum concentration of Bupropion can be decreased when it is combined with Vadadustat. •Extended Description: Vadadustat is a mild inducer of CYP2B6. Therefore, the co-administration of vadadustat with sensitive substrates of CYP2B6 may alter their pharmacokinetics and decrease their concentration. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vadadustat is indicated for the treatment of symptomatic anemia associated with chronic kidney disease (CKD) in adults on chronic maintenance dialysis. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): The use of vadadustat was compared to darbepoetin alfa for the treatment of anemia in adult patients with dialysis-dependent chronic kidney disease. Vadadustat was non-inferior to darbepoetin alfa and met the primary hemoglobin level endpoint. In healthy subjects given 600 mg to 1200 mg of vadadustat, the use of this drug was not associated with clinically significant QTc prolongation. Compared to darbepoetin alfa, patients with dialysis-dependent chronic kidney disease treated with vadadustat have similar risks for death, myocardial infarction and stroke. The use of vadadustat may also lead to the development of thromboembolic events, hepatic impairment, hepatotoxicity, convulsions, as well as an increase in blood pressure. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Hypoxia-inducible factors (HIFs) are transcription factors responsible for cellular survival under hypoxic conditions. They regulate a number of processes including angiogenesis, cell growth and differentiation, various metabolic processes, and erythropoiesis. Under normoxic conditions, HIFs are degraded via hydroxylation by prolyl-hydroxylase dioxygenases. Vadadustat is an inhibitor of HIF-prolyl-hydroxylases (HIF-PHI), that facilitates increased HIF activity in the absence of hypoxic conditions. The increased levels of HIF prompted by vadadustat stimulate endogenous erythropoietin production, increasing iron mobilization and contributing to the gradual rise of hemoglobin levels and the correction of iron metabolism. In patients with anemia of chronic kidney disease, in whom normal erythropoiesis is dysfunctional, this leads to the correction of anemia. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Following single and repeated doses, vadadustat is rapidly absorbed. The T max of vadadustat ranges between 2 and 3 hr. No significant accumulation was detected in healthy subjects given repeated doses of vadadustat. Compared to fasted conditions, the administration of a 450 mg vadadustat tablet with a standard high-fat meal decreased the C max and AUC by 27% and 6%, respectively. Vadadustat may be taken with or without food. The mean blood-to-plasma ratio of vadadustat went from 0.50 to 0.55, suggesting that the sequestration of vadadustat into red blood cells is minimal. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution of vadadustat in patients with chronic kidney disease is 11.6 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The protein binding of vadadustat is greater than or equal to 99.5% in human plasma. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vadadustat is mainly metabolized by UDP-glucuronosyltransferase (UGT) enzymes, forming O-glucuronide conjugates via direct glucuronidation. The metabolism of vadadustat via cytochrome P450s (CYPs) is minimal. The major metabolite of vadadustat is vadadustat-O-glucuronide, which has 15% of the AUC of plasma radioactivity, and it is catalyzed by multiple UGT enzymes, including UGT1A1, UGT1A7, UGT1A8 and UGT1A9. Vadadustat acyl glucuronide is a minor metabolite with 0.047% of the total radioactivity in plasma. None of the vadadustat metabolites are active. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): In healthy subjects given a single dose of 650 mg of radiolabelled vadadustat, 85.9% of the dose was recovered, with 58.9% appearing in urine and 26.9% in feces. Small amounts of the unchanged form of vadadustat are excreted in urine and feces (<1% and 9%, respectively). •Half-life (Drug A): 24 hours •Half-life (Drug B): In patients with dialysis-dependent chronic kidney disease, the half-life of vadadustat was 9.2 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In healthy subjects given a single dose of 300 mg of vadadustat, the apparent total body clearance ranged from 1.7 L/h to 1.9 L/h. In patients with chronic kidney disease, the clearance of vadadustat is 0.8 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): An overdose of vadadustat may lead to extensions of the pharmacologic effects, such as increased hemoglobin levels and secondary polycythemia. In case of overdose, patients should be managed with clinically appropriate measures, such as dose reduction or treatment discontinuation. Patients should be carefully monitored and treated as clinically indicated. Approximately 16% of the vadadustat dose is removed by dialysis. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Vafseo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Vadadustat •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vadadustat is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor used to treat symptomatic anemia associated with chronic kidney disease in adults on chronic maintenance dialysis. Output: Vadadustat is a mild inducer of CYP2B6. Therefore, the co-administration of vadadustat with sensitive substrates of CYP2B6 may alter their pharmacokinetics and decrease their concentration. The severity of the interaction is minor.

Does Bupropion and Valaciclovir interact?

•Drug A: Bupropion •Drug B: Valaciclovir •Severity: MINOR •Description: Valaciclovir may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Valacyclovir is a nucleoside analog DNA polymerase inhibitor indicated for: Adults • Cold Sores (Herpes Labialis) • Genital Herpes • Treatment of genital herpes lesions in immunocompetent patients (initial or recurrent episode) • Suppression of genital herpes lesions in immunocompetent or HIV-infected patients • Reduction of viral transmission • Herpes Zoster Pediatric Patients • Cold Sores (Herpes Labialis) • Chickenpox Limitations of use The efficacy and safety of valacyclovir have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Antiviral effects Valacyclovir shows varying levels of inhibition towards herpes simplex virus types 1 (HSV-1), 2 (HSV-2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response of humans to the same antiviral therapy has not yet been elucidated. Sensitivity testing results, described by the concentration of drug needed to inhibit the growth of the virus by 50% in cell culture (EC50), vary widely depending on various factors. Clinical study results For the various conditions below, clinical study results are summarized as follows: Cold sores Immunocompetent volunteers with cold sores were observed following the administration of a 1-day regimen (2 grams of valacyclovir twice a day for 1 day followed by one day of placebo) or a 2-day regimen (2 grams of valacyclovir twice daily for two days). The average duration of cold sore episodes was approximately 1 day shorter in treated subjects when compared to subjects treated with placebo. A 2-day drug administration regimen of valacyclovir did not provide superior benefit over the 1-day regimen. There was no clinically significant difference observed between subjects receiving valacyclovir or placebo in the prevention of progression of cold sore lesions after the papular stage, indicating that timing of valacyclovir administration is an important consideration. Initial genital herpes episodes 643 immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). In both groups, the median time to healing of herpetic lesions was measured to be 9 days, and the median time to cessation of pain was found to be 5 days, with the median time to cessation of viral shedding was approximately 3 days. Recurrent genital herpes episodes The results of 3 separate studies of patients taking 3 to 5-day regimens of valacyclovir showed an average of 4 days to lesion healing, 2-3 days to resolution of pain associated with the lesions, with an average of 2 days until the cessation of viral shedding. These findings showed valacyclovir administration to show superior beneficial effects when compared to the findings associated with placebo administration. A note on resistance The resistance of Herpes Simplex Virus and Varicella Zoster Virus to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with decreased susceptibility to acyclovir have been isolated from patients diagnosed with AIDS. A total of 522 TK-deficient mutants of VZV have been identified in these cases. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Valacyclovir is the L-valine ester of aciclovir. It is classified as a nucleoside analog DNA polymerase enzyme inhibitor. Aciclovir is a purine (guanine) nucleoside analog is a metabolite that heavily contributes to the pharmacological actions of valacyclovir. In fact, most of valacyclovir's activity is attributed to acyclovir. Valacyclovir is rapidly and almost completely converted in man to aciclovir and valine, likely by the enzyme valacyclovir hydrolase. Aciclovir is a selective inhibitor of the herpes viruses, possessing in vitro activity against herpes simplex viruses (HSV) type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), as well as human herpesvirus 6 (HHV-6). Aciclovir has been shown to inhibit herpes virus DNA synthesis after it has been phosphorylated to the active triphosphate form. The first stage of drug phosphorylation for acyclovir requires activation by a virus-specific enzyme. In the case of HSV, VZV and EBV this enzyme is the viral thymidine kinase (TK), which is only found in virus-infected cells. The process of phosphorylation is completed (conversion from mono- to triphosphate) by cellular kinases. Acyclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this agent results in DNA chain termination, stopping virus DNA synthesis and blocking virus replication. The inhibitory capabilities of acyclovir are highly selective due to the drug's strong affinity for thymidine kinase (TK). In summary, the antiviral effects of valacyclovir are achieved in 3 ways: 1) competitive inhibition of viral DNA polymerase 2) incorporation and termination of the growing viral DNA chain 3) inactivation of the viral DNA polymerase. The higher level of antiviral activity of acyclovir against HSV compared with VZV is attributed to its more efficient phosphorylation by viral thymidine kinase (TK). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal (GI) tract and converted to acyclovir and L-valine. The absolute bioavailability of acyclovir after administration of valacyclovir was measured at 54.5% ± 9.1% after the administration of a 1 gram oral dose of valacyclovir and a 350 mg intravenous (IV) acyclovir dose to 12 healthy subjects. Acyclovir (a metabolite of valacyclovir) bioavailability from the administration of this drug is not affected by the administration with food. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Cerebrospinal fluid (CSF) penetration, determined by CSF/plasma AUC ratio, is approximately 25% for aciclovir and the metabolite 8-hydroxy-aciclovir (8-OH-ACV), and approximately 2.5% for the metabolite 9-(carboxymethoxy)methylguanine. In a study of immunocompromised pediatric patients, the volume of distribution of a 15 ml/kg dose of valacyclovir was 1.34 ± 0.65 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The binding of valacyclovir to human plasma proteins is low and ranges from 13.5% to 17.9%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Valacyclovir is converted to acyclovir and L-valine via first-pass intestinal and/or hepatic metabolism. Acyclovir is also transformed, to a small extent, to inactive metabolites by aldehyde oxidase in addition to alcohol dehydrogenase and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): After oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was measured in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in several studies of valacyclovir in volunteers with normal renal function. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance of acyclovir following the administration of a single 1 gram dose of valacylcovir to 12 healthy 437 volunteers was approximately 255 ± 86 mL/min, which represents 42% of total acyclovir apparent plasma clearance. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD50 Oral Rat – 903.5 mg/kg Carcinogenesis, Mutagenesis, Impairment of Fertility Valacyclovir was noncarcinogenic in lifetime carcinogenicity assays at single daily gavage doses of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. No clinically significant difference in the incidence of tumors between treated and control animals was observed, and valacyclovir was not found to shorten the latency period of tumors. Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. An in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study was negative. In the mouse lymphoma assay, valacyclovir was not found to be mutagenic without metabolic activation, however, in the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic. Valacyclovir was also found to be mutagenic in a mouse micronucleus assay. Valacyclovir did not impair fertility or reproduction in rats at 6 times the normal concentrations in human plasma. Use in pregnancy Valacyclovir is categorized as a pregnancy category B drug. There are insufficient well-controlled studies of valacyclovir in pregnant women. The general rate of birth defects in infants exposed to acyclovir in-utero is comparable to the rate for infants measured in the general population. This drug should be used during pregnancy only if the potential benefit justifies the possible fetal risk. Use in nursing Acyclovir, a major metabolite of valacyclovir, was excreted in breastmilk at lower concentrations when a normal therapeutic dose of valacyclovir was administered. Exercise caution when acyclovir is used while nursing. A note on renal function and toxicity in elderly patients Elderly patients and patients with decreased renal function are at increased risk of valacyclovir toxicity, which can sometimes lead to central nervous system effects, such as encephalopathy, agitation, dysarthria, mania, and psychosis, among other effects. Consider reducing the dose of this drug in these populations to decrease the risk of toxicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Valtrex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Valaciclovir Valaciclovirum Valacyclovir •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valaciclovir is an guanine nucleoside antiviral used to treat herpes exacerbations.

The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Valaciclovir interact? Information: •Drug A: Bupropion •Drug B: Valaciclovir •Severity: MINOR •Description: Valaciclovir may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Valacyclovir is a nucleoside analog DNA polymerase inhibitor indicated for: Adults • Cold Sores (Herpes Labialis) • Genital Herpes • Treatment of genital herpes lesions in immunocompetent patients (initial or recurrent episode) • Suppression of genital herpes lesions in immunocompetent or HIV-infected patients • Reduction of viral transmission • Herpes Zoster Pediatric Patients • Cold Sores (Herpes Labialis) • Chickenpox Limitations of use The efficacy and safety of valacyclovir have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Antiviral effects Valacyclovir shows varying levels of inhibition towards herpes simplex virus types 1 (HSV-1), 2 (HSV-2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response of humans to the same antiviral therapy has not yet been elucidated. Sensitivity testing results, described by the concentration of drug needed to inhibit the growth of the virus by 50% in cell culture (EC50), vary widely depending on various factors. Clinical study results For the various conditions below, clinical study results are summarized as follows: Cold sores Immunocompetent volunteers with cold sores were observed following the administration of a 1-day regimen (2 grams of valacyclovir twice a day for 1 day followed by one day of placebo) or a 2-day regimen (2 grams of valacyclovir twice daily for two days). The average duration of cold sore episodes was approximately 1 day shorter in treated subjects when compared to subjects treated with placebo. A 2-day drug administration regimen of valacyclovir did not provide superior benefit over the 1-day regimen. There was no clinically significant difference observed between subjects receiving valacyclovir or placebo in the prevention of progression of cold sore lesions after the papular stage, indicating that timing of valacyclovir administration is an important consideration. Initial genital herpes episodes 643 immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). In both groups, the median time to healing of herpetic lesions was measured to be 9 days, and the median time to cessation of pain was found to be 5 days, with the median time to cessation of viral shedding was approximately 3 days. Recurrent genital herpes episodes The results of 3 separate studies of patients taking 3 to 5-day regimens of valacyclovir showed an average of 4 days to lesion healing, 2-3 days to resolution of pain associated with the lesions, with an average of 2 days until the cessation of viral shedding. These findings showed valacyclovir administration to show superior beneficial effects when compared to the findings associated with placebo administration. A note on resistance The resistance of Herpes Simplex Virus and Varicella Zoster Virus to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with decreased susceptibility to acyclovir have been isolated from patients diagnosed with AIDS. A total of 522 TK-deficient mutants of VZV have been identified in these cases. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Valacyclovir is the L-valine ester of aciclovir. It is classified as a nucleoside analog DNA polymerase enzyme inhibitor. Aciclovir is a purine (guanine) nucleoside analog is a metabolite that heavily contributes to the pharmacological actions of valacyclovir. In fact, most of valacyclovir's activity is attributed to acyclovir. Valacyclovir is rapidly and almost completely converted in man to aciclovir and valine, likely by the enzyme valacyclovir hydrolase. Aciclovir is a selective inhibitor of the herpes viruses, possessing in vitro activity against herpes simplex viruses (HSV) type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), as well as human herpesvirus 6 (HHV-6). Aciclovir has been shown to inhibit herpes virus DNA synthesis after it has been phosphorylated to the active triphosphate form. The first stage of drug phosphorylation for acyclovir requires activation by a virus-specific enzyme. In the case of HSV, VZV and EBV this enzyme is the viral thymidine kinase (TK), which is only found in virus-infected cells. The process of phosphorylation is completed (conversion from mono- to triphosphate) by cellular kinases. Acyclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this agent results in DNA chain termination, stopping virus DNA synthesis and blocking virus replication. The inhibitory capabilities of acyclovir are highly selective due to the drug's strong affinity for thymidine kinase (TK). In summary, the antiviral effects of valacyclovir are achieved in 3 ways: 1) competitive inhibition of viral DNA polymerase 2) incorporation and termination of the growing viral DNA chain 3) inactivation of the viral DNA polymerase. The higher level of antiviral activity of acyclovir against HSV compared with VZV is attributed to its more efficient phosphorylation by viral thymidine kinase (TK). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal (GI) tract and converted to acyclovir and L-valine. The absolute bioavailability of acyclovir after administration of valacyclovir was measured at 54.5% ± 9.1% after the administration of a 1 gram oral dose of valacyclovir and a 350 mg intravenous (IV) acyclovir dose to 12 healthy subjects. Acyclovir (a metabolite of valacyclovir) bioavailability from the administration of this drug is not affected by the administration with food. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Cerebrospinal fluid (CSF) penetration, determined by CSF/plasma AUC ratio, is approximately 25% for aciclovir and the metabolite 8-hydroxy-aciclovir (8-OH-ACV), and approximately 2.5% for the metabolite 9-(carboxymethoxy)methylguanine. In a study of immunocompromised pediatric patients, the volume of distribution of a 15 ml/kg dose of valacyclovir was 1.34 ± 0.65 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The binding of valacyclovir to human plasma proteins is low and ranges from 13.5% to 17.9%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Valacyclovir is converted to acyclovir and L-valine via first-pass intestinal and/or hepatic metabolism. Acyclovir is also transformed, to a small extent, to inactive metabolites by aldehyde oxidase in addition to alcohol dehydrogenase and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): After oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was measured in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in several studies of valacyclovir in volunteers with normal renal function. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance of acyclovir following the administration of a single 1 gram dose of valacylcovir to 12 healthy 437 volunteers was approximately 255 ± 86 mL/min, which represents 42% of total acyclovir apparent plasma clearance. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD50 Oral Rat – 903.5 mg/kg Carcinogenesis, Mutagenesis, Impairment of Fertility Valacyclovir was noncarcinogenic in lifetime carcinogenicity assays at single daily gavage doses of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. No clinically significant difference in the incidence of tumors between treated and control animals was observed, and valacyclovir was not found to shorten the latency period of tumors. Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. An in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study was negative. In the mouse lymphoma assay, valacyclovir was not found to be mutagenic without metabolic activation, however, in the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic. Valacyclovir was also found to be mutagenic in a mouse micronucleus assay. Valacyclovir did not impair fertility or reproduction in rats at 6 times the normal concentrations in human plasma. Use in pregnancy Valacyclovir is categorized as a pregnancy category B drug. There are insufficient well-controlled studies of valacyclovir in pregnant women. The general rate of birth defects in infants exposed to acyclovir in-utero is comparable to the rate for infants measured in the general population. This drug should be used during pregnancy only if the potential benefit justifies the possible fetal risk. Use in nursing Acyclovir, a major metabolite of valacyclovir, was excreted in breastmilk at lower concentrations when a normal therapeutic dose of valacyclovir was administered. Exercise caution when acyclovir is used while nursing. A note on renal function and toxicity in elderly patients Elderly patients and patients with decreased renal function are at increased risk of valacyclovir toxicity, which can sometimes lead to central nervous system effects, such as encephalopathy, agitation, dysarthria, mania, and psychosis, among other effects. Consider reducing the dose of this drug in these populations to decrease the risk of toxicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Valtrex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Valaciclovir Valaciclovirum Valacyclovir •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valaciclovir is an guanine nucleoside antiviral used to treat herpes exacerbations. Output: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Does Bupropion and Valbenazine interact?

•Drug A: Bupropion •Drug B: Valbenazine •Severity: MODERATE •Description: The serum concentration of Valbenazine can be increased when it is combined with Bupropion. •Extended Description: Since [+]-α-HTBZ, a valbenazine metabolite, is metabolized by CYP2D6, the co-administration of valbenazine with a strong CYP2D6 inhibitor can increase the exposure to valbenazine and thus increase the risk of exposure-related adverse reactions. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Valbenazine is indicated for the treatment of adults with tardive dyskinesia and chorea associated with Huntington’s disease. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable binding affinity for VMAT1 (Ki > 10 µM). Valbenazine is converted to the active metabolite [+]-α-dihydrotetrabenazine ([+]-α-HTBZ). [+]-α-HTBZ also binds with relatively high affinity to human VMAT2 (Ki ~ 3 nM). Valbenazine and [+]-αHTBZ have no appreciable binding affinity (Ki > 5000 nM) for dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic or muscarinic receptors, thus limiting off-target receptors binding for a more favorable safety profile. Valbenazine may cause an increase in the corrected QT interval in patients who are CYP2D6-poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor. An exposure-response analysis of clinical data from two healthy volunteer studies revealed increased QTc interval with higher plasma concentrations of the active metabolite. Based on this model, patients taking an valbenazine 60 mg or 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean (upper bound of double-sided 90% CI) QT prolongation of 9.6 (12.0) msec or 11.7 (14.7) msec, respectively as compared to otherwise healthy volunteers given valbenazine, who had a respective mean (upper bound of double-sided 90% CI) QT prolongation of 5.3 (6.7) msec or 6.7 (8.4) msec. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Although the exact mechanism of action of valbenzine is still unknown, it is thought be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Valbenazine and its active metabolite ([+]-α-HTBZ) demonstrate approximate proportional increases for the area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (C max ) after single oral doses from 40 mg to 300 mg (i.e., 50% to 375% of the recommended treatment dose). Following oral administration, the time to reach maximum valbenazine plasma concentration (T max ) ranges from 0.5 to 1.0 hours. Valbenazine reaches steady-state plasma concentrations within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. [+]-α-HTBZ gradually forms and reaches C max 4 to 8 hours after administration of valbenazine. Ingestion of a high-fat meal decreases valbenazine Cmax by approximately 47% and AUC by approximately 13%. [+]-α-HTBZ Cmax and AUC are unaffected. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean steady-state volume of distribution of valbenazine is 92 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The plasma protein binding of valbenazine and [+]-α-HTBZ is greater than 99% and approximately 64%, respectively. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Valbenazine is extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite ([+]-α-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites. [+]-α-HTBZ appears to be further metabolized in part by CYP2D6. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following the administration of a single 50-mg oral dose of radiolabeled C-valbenazine (i.e., ~63% of the recommended treatment dose), approximately 60% and 30% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 2% was excreted as unchanged valbenazine or [+]-α-HTBZ in either urine or feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): Both Valbenazine and [+]-α-HTBZ have half-lives of 15 to 22 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Valbenazine has a mean total plasma systemic clearance value of 7.2 L/hr. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The limited available data on valbenazine use in pregnant women are insufficient to inform a drug-associated risk. In animal reproductive studies, no malformations were observed when valbenazine was administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on mg/m2 body surface area. However, administration of valbenazine to pregnant rats during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses <1 times the MRHD based on mg/m. Advise a pregnant woman of the potential risk to a fetus. In a fertility study, rats were treated orally with valbenazine at 1, 3, and 10 mg/kg/day prior to mating and through mating, for a minimum of 10 weeks (males) or through Day 7 of gestation (females). These doses are 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m, respectively. Valbenazine delayed mating in both sexes, which led to a lower number of pregnancies and disrupted estrous cyclicity at the high dose, 1.2 times the MRHD of 80 mg/day based on mg/m. Valbenazine had no effects on sperm parameters (motility, count, density) or on uterine parameters (corpora lutea, number of implants, viable implants, pre-implantation loss, early resorptions, and post-implantation loss) at any dose. Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function. Valbenazine did not increase tumors in rats treated orally for 91 weeks at 0.5, 1, and 2 mg/kg/day. These doses are <1 times (0.06, 0.1, and 0.24 times, respectively) the MRHD of 80 mg/day based on mg/m. Valbenazine did not increase tumors in hemizygous Tg.rasH2 mice treated orally for 26 weeks at 10, 30, and 75 mg/kg/day, which are 0.6, 1.9, and 4.6 times the MRHD of 80 mg/day based on mg/m. Valbenazine was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay. No specific antidotes for valbenazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Ingrezza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valbenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia and chorea associated with Huntington's disease.

Since [+]-α-HTBZ, a valbenazine metabolite, is metabolized by CYP2D6, the co-administration of valbenazine with a strong CYP2D6 inhibitor can increase the exposure to valbenazine and thus increase the risk of exposure-related adverse reactions. The severity of the interaction is moderate.

Question: Does Bupropion and Valbenazine interact? Information: •Drug A: Bupropion •Drug B: Valbenazine •Severity: MODERATE •Description: The serum concentration of Valbenazine can be increased when it is combined with Bupropion. •Extended Description: Since [+]-α-HTBZ, a valbenazine metabolite, is metabolized by CYP2D6, the co-administration of valbenazine with a strong CYP2D6 inhibitor can increase the exposure to valbenazine and thus increase the risk of exposure-related adverse reactions. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Valbenazine is indicated for the treatment of adults with tardive dyskinesia and chorea associated with Huntington’s disease. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable binding affinity for VMAT1 (Ki > 10 µM). Valbenazine is converted to the active metabolite [+]-α-dihydrotetrabenazine ([+]-α-HTBZ). [+]-α-HTBZ also binds with relatively high affinity to human VMAT2 (Ki ~ 3 nM). Valbenazine and [+]-αHTBZ have no appreciable binding affinity (Ki > 5000 nM) for dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic or muscarinic receptors, thus limiting off-target receptors binding for a more favorable safety profile. Valbenazine may cause an increase in the corrected QT interval in patients who are CYP2D6-poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor. An exposure-response analysis of clinical data from two healthy volunteer studies revealed increased QTc interval with higher plasma concentrations of the active metabolite. Based on this model, patients taking an valbenazine 60 mg or 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean (upper bound of double-sided 90% CI) QT prolongation of 9.6 (12.0) msec or 11.7 (14.7) msec, respectively as compared to otherwise healthy volunteers given valbenazine, who had a respective mean (upper bound of double-sided 90% CI) QT prolongation of 5.3 (6.7) msec or 6.7 (8.4) msec. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Although the exact mechanism of action of valbenzine is still unknown, it is thought be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Valbenazine and its active metabolite ([+]-α-HTBZ) demonstrate approximate proportional increases for the area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (C max ) after single oral doses from 40 mg to 300 mg (i.e., 50% to 375% of the recommended treatment dose). Following oral administration, the time to reach maximum valbenazine plasma concentration (T max ) ranges from 0.5 to 1.0 hours. Valbenazine reaches steady-state plasma concentrations within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. [+]-α-HTBZ gradually forms and reaches C max 4 to 8 hours after administration of valbenazine. Ingestion of a high-fat meal decreases valbenazine Cmax by approximately 47% and AUC by approximately 13%. [+]-α-HTBZ Cmax and AUC are unaffected. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean steady-state volume of distribution of valbenazine is 92 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The plasma protein binding of valbenazine and [+]-α-HTBZ is greater than 99% and approximately 64%, respectively. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Valbenazine is extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite ([+]-α-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites. [+]-α-HTBZ appears to be further metabolized in part by CYP2D6. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following the administration of a single 50-mg oral dose of radiolabeled C-valbenazine (i.e., ~63% of the recommended treatment dose), approximately 60% and 30% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 2% was excreted as unchanged valbenazine or [+]-α-HTBZ in either urine or feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): Both Valbenazine and [+]-α-HTBZ have half-lives of 15 to 22 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Valbenazine has a mean total plasma systemic clearance value of 7.2 L/hr. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The limited available data on valbenazine use in pregnant women are insufficient to inform a drug-associated risk. In animal reproductive studies, no malformations were observed when valbenazine was administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on mg/m2 body surface area. However, administration of valbenazine to pregnant rats during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses <1 times the MRHD based on mg/m. Advise a pregnant woman of the potential risk to a fetus. In a fertility study, rats were treated orally with valbenazine at 1, 3, and 10 mg/kg/day prior to mating and through mating, for a minimum of 10 weeks (males) or through Day 7 of gestation (females). These doses are 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m, respectively. Valbenazine delayed mating in both sexes, which led to a lower number of pregnancies and disrupted estrous cyclicity at the high dose, 1.2 times the MRHD of 80 mg/day based on mg/m. Valbenazine had no effects on sperm parameters (motility, count, density) or on uterine parameters (corpora lutea, number of implants, viable implants, pre-implantation loss, early resorptions, and post-implantation loss) at any dose. Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function. Valbenazine did not increase tumors in rats treated orally for 91 weeks at 0.5, 1, and 2 mg/kg/day. These doses are <1 times (0.06, 0.1, and 0.24 times, respectively) the MRHD of 80 mg/day based on mg/m. Valbenazine did not increase tumors in hemizygous Tg.rasH2 mice treated orally for 26 weeks at 10, 30, and 75 mg/kg/day, which are 0.6, 1.9, and 4.6 times the MRHD of 80 mg/day based on mg/m. Valbenazine was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay. No specific antidotes for valbenazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Ingrezza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valbenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia and chorea associated with Huntington's disease. Output: Since [+]-α-HTBZ, a valbenazine metabolite, is metabolized by CYP2D6, the co-administration of valbenazine with a strong CYP2D6 inhibitor can increase the exposure to valbenazine and thus increase the risk of exposure-related adverse reactions. The severity of the interaction is moderate.

Does Bupropion and Valdecoxib interact?

•Drug A: Bupropion •Drug B: Valdecoxib •Severity: MINOR •Description: Valdecoxib may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of osteoarthritis and dysmenorrhoea •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, valdecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, valdecoxib does not inhibit platelet aggregation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Oral bioavailability is 83%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 86 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 98% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic (involves CYP3A4 and 2C9) •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide. •Half-life (Drug A): 24 hours •Half-life (Drug B): 8-11 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): oral cl=6 L/h 6 – 7 L/h [In patients undergoing hemodialysis] 6 – 7 L/h [healthy elderly subjects] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Bextra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valdecoxib is a COX-2 inhibitor used to treat osteoarthritis and dysmenorrhoea.

The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Valdecoxib interact? Information: •Drug A: Bupropion •Drug B: Valdecoxib •Severity: MINOR •Description: Valdecoxib may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of osteoarthritis and dysmenorrhoea •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, valdecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, valdecoxib does not inhibit platelet aggregation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Oral bioavailability is 83%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 86 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 98% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic (involves CYP3A4 and 2C9) •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide. •Half-life (Drug A): 24 hours •Half-life (Drug B): 8-11 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): oral cl=6 L/h 6 – 7 L/h [In patients undergoing hemodialysis] 6 – 7 L/h [healthy elderly subjects] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Bextra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valdecoxib is a COX-2 inhibitor used to treat osteoarthritis and dysmenorrhoea. Output: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Does Bupropion and Valganciclovir interact?

•Drug A: Bupropion •Drug B: Valganciclovir •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Valganciclovir. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Valganciclovir is an antiviral medication used for the treatment of cytomegalovirus infections. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Valganciclovir is an antiviral medication used to treat cytomegalovirus infections. As the L-valyl ester of ganciclovir, it is actually a prodrug for ganciclovir. After oral administration, it is rapidly converted to ganciclovir by intestinal and hepatic esterases. After this, it (being an analogue of guanosine) gets incorporated into DNA and thus cannot be properly read by DNA polymerase. This results in the termination of the elongation of viral DNA. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Valganciclovir is a prodrug of ganciclovir that exists as a mixture of two diastereomers. After administration, these diastereomers are rapidly converted to ganciclovir by hepatic and intestinal esterases. In cytomegalovirus (CMV)-infected cells, ganciclovir is initially phosphorylated to the monophosphate form by viral protein kinase, then it is further phosphorylated via cellular kinases to produce the triphosphate form. This triphosphate form is slowly metabolized intracellularly. The phosphorylation is dependent upon the viral kinase and occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to the inhibition of viral DNA synthesis by ganciclovir triphosphate. Ganciclovir triphosphate is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand. Ganciclovir inhibits viral DNA polymerases more effectively than it does cellular polymerase, and chain elongation resumes when ganciclovir is removed. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Valganciclovir is well absorbed from the gastrointestinal tract and the absolute bioavailability from valganciclovir tablets (following administration with food) is approximately 60%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 0.703 ± 0.134 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51 mg/mL. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Rapidly hydrolyzed in the intestinal wall and liver to ganciclovir. No other metabolites have been detected. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. •Half-life (Drug A): 24 hours •Half-life (Drug B): Approximately 4.08 hours. Increased in patients with renal function impairment. •Clearance (Drug A): No clearance available •Clearance (Drug B): 3.07+/- 0.64 mL/min/kg [IV administration] 5.3 L/hr [Patient with creatinine clearance of 70.4 mL/min] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): It is expected that an overdose of valganciclovir could also possibly result in increased renal toxicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Valcyte •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valganciclovir is an antiviral medication used to treat cytomegalovirus (CMV) retinitis in patients diagnosed with acquired immunodeficiency syndrome (AIDS).

Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Question: Does Bupropion and Valganciclovir interact? Information: •Drug A: Bupropion •Drug B: Valganciclovir •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Valganciclovir. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Valganciclovir is an antiviral medication used for the treatment of cytomegalovirus infections. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Valganciclovir is an antiviral medication used to treat cytomegalovirus infections. As the L-valyl ester of ganciclovir, it is actually a prodrug for ganciclovir. After oral administration, it is rapidly converted to ganciclovir by intestinal and hepatic esterases. After this, it (being an analogue of guanosine) gets incorporated into DNA and thus cannot be properly read by DNA polymerase. This results in the termination of the elongation of viral DNA. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Valganciclovir is a prodrug of ganciclovir that exists as a mixture of two diastereomers. After administration, these diastereomers are rapidly converted to ganciclovir by hepatic and intestinal esterases. In cytomegalovirus (CMV)-infected cells, ganciclovir is initially phosphorylated to the monophosphate form by viral protein kinase, then it is further phosphorylated via cellular kinases to produce the triphosphate form. This triphosphate form is slowly metabolized intracellularly. The phosphorylation is dependent upon the viral kinase and occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to the inhibition of viral DNA synthesis by ganciclovir triphosphate. Ganciclovir triphosphate is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand. Ganciclovir inhibits viral DNA polymerases more effectively than it does cellular polymerase, and chain elongation resumes when ganciclovir is removed. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Valganciclovir is well absorbed from the gastrointestinal tract and the absolute bioavailability from valganciclovir tablets (following administration with food) is approximately 60%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 0.703 ± 0.134 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51 mg/mL. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Rapidly hydrolyzed in the intestinal wall and liver to ganciclovir. No other metabolites have been detected. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. •Half-life (Drug A): 24 hours •Half-life (Drug B): Approximately 4.08 hours. Increased in patients with renal function impairment. •Clearance (Drug A): No clearance available •Clearance (Drug B): 3.07+/- 0.64 mL/min/kg [IV administration] 5.3 L/hr [Patient with creatinine clearance of 70.4 mL/min] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): It is expected that an overdose of valganciclovir could also possibly result in increased renal toxicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Valcyte •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valganciclovir is an antiviral medication used to treat cytomegalovirus (CMV) retinitis in patients diagnosed with acquired immunodeficiency syndrome (AIDS). Output: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Does Bupropion and Valproic acid interact?

•Drug A: Bupropion •Drug B: Valproic acid •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Valproic acid is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated for: 1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures. 2) Adjunctive therapy in the management of multiple seizure types that include absence seizures. 3) Prophylaxis of migraine headaches. 4) Acute management of mania associated with bipolar disorder. Off-label uses include: 1) Maintenance therapy for bipolar disorder. 2) Treatment for acute bipolar depression. 3) Emergency treatment of status epilepticus. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches. It also improves symptom control in bipolar mania. Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder. Valproate is hepatotoxic and teratogenic. The reasons for this are unclear but have been attributed to the genomic effects of the drug. A small proof-of concept study found that valproate increases clearance of human immunodeficiency virus (HIV) when combined with highly active antiretroviral therapy (HAART) by reactivating the virus to allow clearance, however, a larger multicentre trial failed to show a significant effect on HIV reservoirs when added to HAART. The FDA labeling contains a warning regarding HIV reactivation during valproate use.. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action. Valproate is known to inhibit succinic semialdehyde dehydrogenase. This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity. A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA. It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK). These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABA A receptors which contribute further to increased GABAergic activity. Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase. This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect. Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium. The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis. Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton. Valproate also appears to impact fatty acid metabolism. Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action. Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase. Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production. Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor. Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated. The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients. Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong. H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective effects. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state. The oral delayed-release tablet formulation has a Tmax of 4 hours. Differences in absorption rate are expected from other formulations but are not considered to be clinically important in the context of chronic therapy beyond impacting frequency of dosing. Differences in absorption may create earlier Tmax or higher Cmax values on initiation of therapy and may be affected differently by meals. The extended release tablet formulation had Tmax increase from 4 hours to 8 hours when taken with food. In comparison, the sprinkle capsule formulation had Tmax increase from 3.3 hours to 4.8 hours. Bioavailability is reported to be approximately 90% with all oral formulations with enteric-coated forms possibly reaching 100%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 11 L/1.73m. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Protein binding is linear at low concentrations with a free fraction of approximately 10% at 40 mcg/mL but becomes non-linear at higher concentrations with a free fraction of 18.5% at 135 mcg/mL. This may be due to binding at separate high and low-affinity sites on albumin proteins. Binding is expected to decrease in the elderly and patients with hepatic dysfunction. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Most drug is metabolized to glucuronide conjugates (30-50%) of the parent drug or of metabolites. Another large portion is metabolized through mitochondrial β-oxidation (40%). The remainder of metabolism (15-20%) occurs through oxidation, hydroxylation, and dehydrogenation at the ω, ω 1, and ω 2 positions resulting in the formation of hydroxyls, ketones, carboxyls, a lactone metabolite, double bonds, and combinations. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Most drug is eliminated through hepatic metabolism, about 30-50%. The other major contributing pathway is mitochondrial β-oxidation, about 40%. Other oxidative pathways make up an additional 15-20%. Less than 3% is excreted unchanged in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): 13-19 hours. The half-life in neonates ranges from 10-67 hours while the half-life in pediatric patients under 2 months of age ranges from 7-13 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.56 L/hr/m Pediatric patients between 3 months and 10 years of age have 50% higher clearances by weight. Pediatric patients 10 years of age or older approximate adult values. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD 50 Values Oral, mouse: 1098 mg/kg Oral, rat: 670 mg/kg Overdose Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. The unbound fraction may be removed by hemodialysis. Naloxone has been demonstrated to reverse the CNS depressant effects of overdose but may also reverse the anti-epileptic effects. Reproductive Toxicity Valproate use in pregnancy is known to increase the risk of neural tube defects and other structural abnormalities. The risk of spina bifida increases from 0.06-0.07% in the normal population to 1-2% in valproate users. The North American Antiepileptic Drug (NAAED) Pregnancy Registry reports a major malformation rate of 9-11%, 5 times the baseline rate. These malformations include neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems. Other antiepileptic drugs, lamotrigine, carbemazepine, and phenytoin, have been found to reduce IQ in children exposed in utero. Valproate was also studied however the results did not achieve statistical significance (97 IQ (CI: 94-101)). Observational studies report an absolute risk increase of 2.9% (relative risk 2.9 times baseline) of autism spectrum disorder in children exposed to valproate in utero. There have been case reports of fatal hepatic failure in children of mothers who used valproate during pregnancy. There have been reports of male infertility when taking valproate. Lactation Valproate is excreted in human milk. Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk. Other Toxicity Considerations Use in pediatrics under 2 years of age increases the risk of fatal hepatotoxicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Depakene, Depakote, Epival •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): acide valproïque ácido valproico acidum valproicum Dipropylacetic acid Valproate Valproic acid Valproinsäure •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valproic acid is an anticonvulsant used to control complex partial seizures and both simple and complex absence seizures.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Valproic acid interact? Information: •Drug A: Bupropion •Drug B: Valproic acid •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Valproic acid is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated for: 1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures. 2) Adjunctive therapy in the management of multiple seizure types that include absence seizures. 3) Prophylaxis of migraine headaches. 4) Acute management of mania associated with bipolar disorder. Off-label uses include: 1) Maintenance therapy for bipolar disorder. 2) Treatment for acute bipolar depression. 3) Emergency treatment of status epilepticus. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches. It also improves symptom control in bipolar mania. Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder. Valproate is hepatotoxic and teratogenic. The reasons for this are unclear but have been attributed to the genomic effects of the drug. A small proof-of concept study found that valproate increases clearance of human immunodeficiency virus (HIV) when combined with highly active antiretroviral therapy (HAART) by reactivating the virus to allow clearance, however, a larger multicentre trial failed to show a significant effect on HIV reservoirs when added to HAART. The FDA labeling contains a warning regarding HIV reactivation during valproate use.. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action. Valproate is known to inhibit succinic semialdehyde dehydrogenase. This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity. A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA. It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK). These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABA A receptors which contribute further to increased GABAergic activity. Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase. This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect. Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium. The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis. Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton. Valproate also appears to impact fatty acid metabolism. Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action. Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase. Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production. Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor. Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated. The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients. Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong. H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective effects. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state. The oral delayed-release tablet formulation has a Tmax of 4 hours. Differences in absorption rate are expected from other formulations but are not considered to be clinically important in the context of chronic therapy beyond impacting frequency of dosing. Differences in absorption may create earlier Tmax or higher Cmax values on initiation of therapy and may be affected differently by meals. The extended release tablet formulation had Tmax increase from 4 hours to 8 hours when taken with food. In comparison, the sprinkle capsule formulation had Tmax increase from 3.3 hours to 4.8 hours. Bioavailability is reported to be approximately 90% with all oral formulations with enteric-coated forms possibly reaching 100%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 11 L/1.73m. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Protein binding is linear at low concentrations with a free fraction of approximately 10% at 40 mcg/mL but becomes non-linear at higher concentrations with a free fraction of 18.5% at 135 mcg/mL. This may be due to binding at separate high and low-affinity sites on albumin proteins. Binding is expected to decrease in the elderly and patients with hepatic dysfunction. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Most drug is metabolized to glucuronide conjugates (30-50%) of the parent drug or of metabolites. Another large portion is metabolized through mitochondrial β-oxidation (40%). The remainder of metabolism (15-20%) occurs through oxidation, hydroxylation, and dehydrogenation at the ω, ω 1, and ω 2 positions resulting in the formation of hydroxyls, ketones, carboxyls, a lactone metabolite, double bonds, and combinations. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Most drug is eliminated through hepatic metabolism, about 30-50%. The other major contributing pathway is mitochondrial β-oxidation, about 40%. Other oxidative pathways make up an additional 15-20%. Less than 3% is excreted unchanged in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): 13-19 hours. The half-life in neonates ranges from 10-67 hours while the half-life in pediatric patients under 2 months of age ranges from 7-13 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.56 L/hr/m Pediatric patients between 3 months and 10 years of age have 50% higher clearances by weight. Pediatric patients 10 years of age or older approximate adult values. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD 50 Values Oral, mouse: 1098 mg/kg Oral, rat: 670 mg/kg Overdose Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. The unbound fraction may be removed by hemodialysis. Naloxone has been demonstrated to reverse the CNS depressant effects of overdose but may also reverse the anti-epileptic effects. Reproductive Toxicity Valproate use in pregnancy is known to increase the risk of neural tube defects and other structural abnormalities. The risk of spina bifida increases from 0.06-0.07% in the normal population to 1-2% in valproate users. The North American Antiepileptic Drug (NAAED) Pregnancy Registry reports a major malformation rate of 9-11%, 5 times the baseline rate. These malformations include neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems. Other antiepileptic drugs, lamotrigine, carbemazepine, and phenytoin, have been found to reduce IQ in children exposed in utero. Valproate was also studied however the results did not achieve statistical significance (97 IQ (CI: 94-101)). Observational studies report an absolute risk increase of 2.9% (relative risk 2.9 times baseline) of autism spectrum disorder in children exposed to valproate in utero. There have been case reports of fatal hepatic failure in children of mothers who used valproate during pregnancy. There have been reports of male infertility when taking valproate. Lactation Valproate is excreted in human milk. Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk. Other Toxicity Considerations Use in pediatrics under 2 years of age increases the risk of fatal hepatotoxicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Depakene, Depakote, Epival •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): acide valproïque ácido valproico acidum valproicum Dipropylacetic acid Valproate Valproic acid Valproinsäure •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valproic acid is an anticonvulsant used to control complex partial seizures and both simple and complex absence seizures. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Valsartan interact?

•Drug A: Bupropion •Drug B: Valsartan •Severity: MODERATE •Description: The metabolism of Bupropion can be decreased when combined with Valsartan. •Extended Description: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Valsartan is indicated for the treatment of hypertension to reduce the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. It is also indicated for the treatment of heart failure (NYHA class II-IV) and for left ventricular dysfunction or failure after myocardial infarction when the use of an angiotensin-converting enzyme inhibitor (ACEI) is not appropriate. It is also used in combination with sacubitril. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Valsartan inhibits the pressor effects of angiotensin II with oral doses of 80 mg inhibiting the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan. In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. Hypotension Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision. Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan. Hyperkalemia Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan may be required. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which selectively bind to angiotensin receptor 1 (AT1) and prevent angiotensin II from binding and exerting its hypertensive effects. These include vasoconstriction, stimulation and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium among others. Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. Valsartan also affects the renin-angiotensin aldosterone system (RAAS), which plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and prevent ventricular hypertrophy. The angiotensin-converting enzyme inhibitor (ACEI) class of medications (which includes drugs such as ramipril, lisinopril, and perindopril ) inhibits the conversion of angiotensin I to angiotensin II by inhibiting the ACE enzyme but does not prevent the formation of all angiotensin II. ARB activity is unique in that it blocks all angiotensin II activity, regardless of where or how it was synthesized. Valsartan is commonly used for the management of hypertension, heart failure, and type 2 diabetes-associated nephropathy, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as valsartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Valsartan also slows the progression of diabetic nephropathy due to its renoprotective effects. Improvements in chronic kidney disease with valsartan include both clinically and statistically significant decreases in urinary albumin and protein excretion in patients diagnosed with type 2 diabetes and in nondiabetic patients diagnosed with chronic kidney disease. Valsartan also binds to the AT2 receptor, however AT2 is not known to be associated with cardiovascular homeostasis like AT1. Valsartan has about 20,000-fold higher affinity for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients. Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan generally increase linearly with increasing dose over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The steady-state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Valsartan is highly bound to serum proteins (95%), mainly serum albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. •Half-life (Drug A): 24 hours •Half-life (Drug B): After intravenous (IV) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 6 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total clearance). •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Approximate LD50 >2000 mg/kg (Gavage, rat) Reproductive Toxicology Studies No teratogenic effects were seen when valsartan was given to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses reaching up to 10 mg/kg/day. Despite this, marked decreases in fetal weight, pup birth weight, pup survival rate, and delays in developmental milestones were noted in studies in which parental rats were treated with valsartan at oral, maternally toxic doses of 600 mg/kg/day during the organogenesis period or during late gestation and lactation. Pregnancy When used in pregnancy, drugs that act directly on the renin-angiotensin system (RAAS) can cause injury and death to the developing fetus. When pregnancy is detected, valsartan should be discontinued as soon as possible. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Dafiro, Diovan, Diovan Hct, Entresto, Exforge, Exforge Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Valsartan •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valsartan is an angiotensin-receptor blocker used to manage hypertension alone or in combination with other antihypertensive agents and to manage heart failure in patients who are intolerant to ACE inhibitors.

The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is moderate.

Question: Does Bupropion and Valsartan interact? Information: •Drug A: Bupropion •Drug B: Valsartan •Severity: MODERATE •Description: The metabolism of Bupropion can be decreased when combined with Valsartan. •Extended Description: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Valsartan is indicated for the treatment of hypertension to reduce the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. It is also indicated for the treatment of heart failure (NYHA class II-IV) and for left ventricular dysfunction or failure after myocardial infarction when the use of an angiotensin-converting enzyme inhibitor (ACEI) is not appropriate. It is also used in combination with sacubitril. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Valsartan inhibits the pressor effects of angiotensin II with oral doses of 80 mg inhibiting the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan. In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. Hypotension Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision. Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan. Hyperkalemia Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan may be required. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which selectively bind to angiotensin receptor 1 (AT1) and prevent angiotensin II from binding and exerting its hypertensive effects. These include vasoconstriction, stimulation and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium among others. Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. Valsartan also affects the renin-angiotensin aldosterone system (RAAS), which plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and prevent ventricular hypertrophy. The angiotensin-converting enzyme inhibitor (ACEI) class of medications (which includes drugs such as ramipril, lisinopril, and perindopril ) inhibits the conversion of angiotensin I to angiotensin II by inhibiting the ACE enzyme but does not prevent the formation of all angiotensin II. ARB activity is unique in that it blocks all angiotensin II activity, regardless of where or how it was synthesized. Valsartan is commonly used for the management of hypertension, heart failure, and type 2 diabetes-associated nephropathy, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as valsartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Valsartan also slows the progression of diabetic nephropathy due to its renoprotective effects. Improvements in chronic kidney disease with valsartan include both clinically and statistically significant decreases in urinary albumin and protein excretion in patients diagnosed with type 2 diabetes and in nondiabetic patients diagnosed with chronic kidney disease. Valsartan also binds to the AT2 receptor, however AT2 is not known to be associated with cardiovascular homeostasis like AT1. Valsartan has about 20,000-fold higher affinity for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients. Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan generally increase linearly with increasing dose over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The steady-state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Valsartan is highly bound to serum proteins (95%), mainly serum albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. •Half-life (Drug A): 24 hours •Half-life (Drug B): After intravenous (IV) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 6 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total clearance). •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Approximate LD50 >2000 mg/kg (Gavage, rat) Reproductive Toxicology Studies No teratogenic effects were seen when valsartan was given to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses reaching up to 10 mg/kg/day. Despite this, marked decreases in fetal weight, pup birth weight, pup survival rate, and delays in developmental milestones were noted in studies in which parental rats were treated with valsartan at oral, maternally toxic doses of 600 mg/kg/day during the organogenesis period or during late gestation and lactation. Pregnancy When used in pregnancy, drugs that act directly on the renin-angiotensin system (RAAS) can cause injury and death to the developing fetus. When pregnancy is detected, valsartan should be discontinued as soon as possible. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Dafiro, Diovan, Diovan Hct, Entresto, Exforge, Exforge Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Valsartan •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Valsartan is an angiotensin-receptor blocker used to manage hypertension alone or in combination with other antihypertensive agents and to manage heart failure in patients who are intolerant to ACE inhibitors. Output: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is moderate.

Does Bupropion and Vancomycin interact?

•Drug A: Bupropion •Drug B: Vancomycin •Severity: MODERATE •Description: Bupropion may decrease the excretion rate of Vancomycin which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Administered intravenously, vancomycin is indicated in adult and pediatric patients for the treatment of septicemia, infective endocarditis, skin and skin structure infections, bone infections, and lower respiratory tract infections. Administered orally, vancomycin is indicated in adult and pediatric patients for the treatment of Clostridium difficile -associated diarrhea and for enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains). •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vancomycin is a branched tricyclic glycosylated nonribosomal peptide often reserved as the "drug of last resort", used only after treatment with other antibiotics has failed. Vancomycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections: Listeria monocytogenes, Streptococcus pyogenes, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus agalactiae, Actinomyces species, and Lactobacillus species. The combination of vancomycin and an aminoglycoside acts synergistically in vitro against many strains of Staphylococcus aureus, Streptococcus bovis, enterococci, and the viridans group streptococci. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix, which forms the major structural component of Gram-positive cell walls. Vancomycin forms hydrogen bonds with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides, preventing the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Poorly absorbed from gastrointestinal tract, however systemic absorption (up to 60%) may occur following intraperitoneal administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution, as discussed in the literature, varies between 0.4-1 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 50% serum protein bound. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Since almost 75-80% of the drug is excreted unchanged in the urine after the first 24 hours following administration, there is seemingly no apparent metabolism of the drug. The concentration of vancomycin in the liver tissue and bile 24 hours after administration has also been reported at or below detection limits as well. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): In the first 24 hours, about 75-80% of an administered dose of vancomycin is excreted in urine by glomerular filtration. •Half-life (Drug A): 24 hours •Half-life (Drug B): Half-life in normal renal patients is approximately 6 hours (range 4 to 11 hours). In anephric patients, the average half-life of elimination is 7.5 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean plasma clearance of vancomycin is about 0.058 L/kg/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 in mice is 5000 mg/kg. The median lethal intravenous dose is 319 mg/kg in rats and 400 mg/kg in mice. Conversely, the most common adverse effects associated with vancomycin appear to be nausea, abdominal pain, and hypokalemia. In particular, incidences of hypokalemia, urinary tracy infection, peripheral edema, insomnia, constipation, anemia, depression, vomiting, and hypotension are higher among subjects >65 years of than in those that are 65 years old or younger. Additionally, nephrotoxicity involving reports of renal failure, renal impairment, elevated blood creatinine, and others has also occurred with vancomycin therapy during studies, and can occur during or after completion of a course of therapy. Risk of such nephrotoxicity is increased in patients greater than 65 years of age. Ototoxicity has also occurred in patients receiving vancomycin treatment, and it can be transient or permanent. This effect has been reported primarily in patients who have been given excessive intravenous doses, who have kidney dysfunction, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent like an aminoglycoside. Potentially related adverse effects like vertigo, dizziness, and tinnitus have also been reported. Neutropenia, often beginning one week or more after onset of intravenous vancomycin therapy or after a total dose of more than 25 mg has been observed for several dozen patients as well. This neutropenia however, appears to be promptly reversible when the vancomycin treatment is discontinued. Alternatively, thrombocytopenia has also been reported. Additionally, a condition has been reported that is described as being similar to IV-induced symptoms involving symptoms consistent with anaphylactoid reactions, including hypotension, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (in what is known as the so-called 'Red Man Syndrome'), pain and muscle spasm of the chest and back. Although on average such reactions usually resolve within 20 minutes, they are just as likely to persist for hours. In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin on infants were assessed when the drug was given intravenously to pregnant women for serious staphylococcal infections complicating intravenous drug abuse. The results obtained demonstrated that vancomycin was found in cord blood but that no sensorineural hearing loss or nephrotoxicity attributable to vancomycin was noted. Ultimately however, because the number of subjects treated in this study was limited and vancomycin was administered only in the second and third trimesters, it is not formally known whether vancomycin causes fetal harm. Subsequently, vancomycin should be given to a pregnant woman only if clearly needed. Although it is known that vancomycin is excreted in human milk based on information obtained from the intravenous administration of the medication, it is not known if vancomycin is excreted into human milk after oral administration. However, because of the overall potential for adverse events, caution must be exercised when vancomycin is given to a nursing woman and a decision must be made whether to discontinue nursing or discontinue the drug, taking into consideration the importance of the drug to the mother. The safety and effectiveness in pediatric patients have not been formally established. Patients older than 65 years of age may take longer to respond to therapy compared to patients aged 65 year or younger. Vancomycin treatment in patients aged older than 65 years subsequently should not be discontinued or switched to an alternative treatment prematurely. Furthermore, clinical studies have demonstrated that geriatric patients are at increased risk of developing nephrotoxicity following treatment with oral vancomycin, which can occur during or after completion of therapy. In patients aged older than 65 years, including those with normal renal function prior to treatment, renal function should be monitored during and following treatment with vancomycin to detect any potential vancomycin induced nephrotoxicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Firvanq, Vancocin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vancomycin is a glycopeptide antibiotic used to treat severe but susceptible bacterial infections such as MRSA (methicillin-resistant Staphylococcus aureus) infections.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. The severity of the interaction is moderate.

Question: Does Bupropion and Vancomycin interact? Information: •Drug A: Bupropion •Drug B: Vancomycin •Severity: MODERATE •Description: Bupropion may decrease the excretion rate of Vancomycin which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Administered intravenously, vancomycin is indicated in adult and pediatric patients for the treatment of septicemia, infective endocarditis, skin and skin structure infections, bone infections, and lower respiratory tract infections. Administered orally, vancomycin is indicated in adult and pediatric patients for the treatment of Clostridium difficile -associated diarrhea and for enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains). •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vancomycin is a branched tricyclic glycosylated nonribosomal peptide often reserved as the "drug of last resort", used only after treatment with other antibiotics has failed. Vancomycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections: Listeria monocytogenes, Streptococcus pyogenes, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus agalactiae, Actinomyces species, and Lactobacillus species. The combination of vancomycin and an aminoglycoside acts synergistically in vitro against many strains of Staphylococcus aureus, Streptococcus bovis, enterococci, and the viridans group streptococci. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix, which forms the major structural component of Gram-positive cell walls. Vancomycin forms hydrogen bonds with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides, preventing the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Poorly absorbed from gastrointestinal tract, however systemic absorption (up to 60%) may occur following intraperitoneal administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution, as discussed in the literature, varies between 0.4-1 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 50% serum protein bound. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Since almost 75-80% of the drug is excreted unchanged in the urine after the first 24 hours following administration, there is seemingly no apparent metabolism of the drug. The concentration of vancomycin in the liver tissue and bile 24 hours after administration has also been reported at or below detection limits as well. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): In the first 24 hours, about 75-80% of an administered dose of vancomycin is excreted in urine by glomerular filtration. •Half-life (Drug A): 24 hours •Half-life (Drug B): Half-life in normal renal patients is approximately 6 hours (range 4 to 11 hours). In anephric patients, the average half-life of elimination is 7.5 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean plasma clearance of vancomycin is about 0.058 L/kg/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 in mice is 5000 mg/kg. The median lethal intravenous dose is 319 mg/kg in rats and 400 mg/kg in mice. Conversely, the most common adverse effects associated with vancomycin appear to be nausea, abdominal pain, and hypokalemia. In particular, incidences of hypokalemia, urinary tracy infection, peripheral edema, insomnia, constipation, anemia, depression, vomiting, and hypotension are higher among subjects >65 years of than in those that are 65 years old or younger. Additionally, nephrotoxicity involving reports of renal failure, renal impairment, elevated blood creatinine, and others has also occurred with vancomycin therapy during studies, and can occur during or after completion of a course of therapy. Risk of such nephrotoxicity is increased in patients greater than 65 years of age. Ototoxicity has also occurred in patients receiving vancomycin treatment, and it can be transient or permanent. This effect has been reported primarily in patients who have been given excessive intravenous doses, who have kidney dysfunction, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent like an aminoglycoside. Potentially related adverse effects like vertigo, dizziness, and tinnitus have also been reported. Neutropenia, often beginning one week or more after onset of intravenous vancomycin therapy or after a total dose of more than 25 mg has been observed for several dozen patients as well. This neutropenia however, appears to be promptly reversible when the vancomycin treatment is discontinued. Alternatively, thrombocytopenia has also been reported. Additionally, a condition has been reported that is described as being similar to IV-induced symptoms involving symptoms consistent with anaphylactoid reactions, including hypotension, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (in what is known as the so-called 'Red Man Syndrome'), pain and muscle spasm of the chest and back. Although on average such reactions usually resolve within 20 minutes, they are just as likely to persist for hours. In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin on infants were assessed when the drug was given intravenously to pregnant women for serious staphylococcal infections complicating intravenous drug abuse. The results obtained demonstrated that vancomycin was found in cord blood but that no sensorineural hearing loss or nephrotoxicity attributable to vancomycin was noted. Ultimately however, because the number of subjects treated in this study was limited and vancomycin was administered only in the second and third trimesters, it is not formally known whether vancomycin causes fetal harm. Subsequently, vancomycin should be given to a pregnant woman only if clearly needed. Although it is known that vancomycin is excreted in human milk based on information obtained from the intravenous administration of the medication, it is not known if vancomycin is excreted into human milk after oral administration. However, because of the overall potential for adverse events, caution must be exercised when vancomycin is given to a nursing woman and a decision must be made whether to discontinue nursing or discontinue the drug, taking into consideration the importance of the drug to the mother. The safety and effectiveness in pediatric patients have not been formally established. Patients older than 65 years of age may take longer to respond to therapy compared to patients aged 65 year or younger. Vancomycin treatment in patients aged older than 65 years subsequently should not be discontinued or switched to an alternative treatment prematurely. Furthermore, clinical studies have demonstrated that geriatric patients are at increased risk of developing nephrotoxicity following treatment with oral vancomycin, which can occur during or after completion of therapy. In patients aged older than 65 years, including those with normal renal function prior to treatment, renal function should be monitored during and following treatment with vancomycin to detect any potential vancomycin induced nephrotoxicity. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Firvanq, Vancocin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vancomycin is a glycopeptide antibiotic used to treat severe but susceptible bacterial infections such as MRSA (methicillin-resistant Staphylococcus aureus) infections. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. The severity of the interaction is moderate.

Does Bupropion and Vardenafil interact?

•Drug A: Bupropion •Drug B: Vardenafil •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Vardenafil. •Extended Description: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vardenafil is indicated for the treatment of erectile dysfunction. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vardenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), an enzyme responsible for the degradation of cGMP in the corpus cavernosum. The presence of cGMP in the corpus cavernosum leads to smooth muscle relaxation, an increased inflow of blood and an erection. Therefore, in patients with erectile dysfunction given vardenafil, normal sexual stimulation will increase cGMP levels in the corpus cavernosum. Without sexual stimulation and no cGMP production, vardenafil should not cause an erection. Vardenafil should not be used in men for whom sexual activity is not recommended due to their underlying cardiovascular status. There is also a risk of developing prolonged erections that last longer than 4 hours, as well as priapism. In the event of a sudden loss of vision in one or both eyes, patients should stop using vardenafil. Patients taking PDE5 inhibitors, such as vardenafil, may also develop sudden hearing loss and experience a prolonged QT interval. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vardenafil inhibits cyclic guanosine monophosphate (GMP) specific phosphodiesterase type 5 (PDE5), which is responsible for the degradation of cyclic GMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic GMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The tissue concentration of cyclic GMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs), and the most abundant PDE in the human corpus cavernosum is PDE5. Therefore, the inhibition of PDE5 by vardenafil enhances erectile function by increasing the amount of cyclic GMP. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Over the recommended dose range, vardenafil has a dose-proportional pharmacokinetics profile. In healthy male volunteers given a single oral dose of 20 mg of vardenafil, maximum plasma concentrations were reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state, and 0.00018% of the dose was detected in semen 1.5 hours after dosing. Vardenafil has a bioavailability of approximately 15%. High-fat meals cause a C max reduction of 18%-50%; however, no changes were detected in AUC or T max. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vardenafil has a steady-state volume of distribution of 208 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 95% of vardenafil and its major circulating metabolite is bound to plasma proteins. Their protein binding is reversible and independent of total drug concentrations. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vardenafil is mainly metabolized by CYP3A4 in the liver, although CYP3A5 and CYP2C isoforms also contribute to its metabolism. The major circulating metabolite, M1 (N-desethylvardenafil), results from desethylation at the piperazine moiety of vardenafil, and has a plasma concentration of approximately 26% of that of the parent compound. M1 has a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Vardenafil is excreted as metabolites mainly through feces and urine. Approximately 91-95% of administered oral dose is found in feces, while 2-6% of administered oral dose is found in urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Vardenafil and its primary metabolite (M1) have a terminal half-life of 4-5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Vardenafil has a total body clearance of 56 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Healthy male volunteers given a single dose of 120 mg of vardenafil experienced reversible back pain, myalgia and abnormal vision. Patients given vardenafil once daily over 4 weeks in single doses up to 80 mg and multiple doses up to 40 mg did not present serious adverse side effects. Cases of severe back pain were observed when 40 mg of vardenafil was administered twice daily; however patients did not present muscle or neurological toxicity. In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance as vardenafil is highly bound to plasma proteins and not significantly eliminated in the urine. No carcinogenic effects were detected in rats and mice given vardenafil daily for 24 months. Vardenafil was not mutagenic or clastogenic, and did not have an effect in fertility in male and female rats given up to 100 mg/kg/day for 28 days prior to mating in males, and for 14 days prior to mating and through day 7 of gestation in females. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Levitra, Staxyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vardenafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction.

Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Vardenafil interact? Information: •Drug A: Bupropion •Drug B: Vardenafil •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Vardenafil. •Extended Description: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vardenafil is indicated for the treatment of erectile dysfunction. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vardenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), an enzyme responsible for the degradation of cGMP in the corpus cavernosum. The presence of cGMP in the corpus cavernosum leads to smooth muscle relaxation, an increased inflow of blood and an erection. Therefore, in patients with erectile dysfunction given vardenafil, normal sexual stimulation will increase cGMP levels in the corpus cavernosum. Without sexual stimulation and no cGMP production, vardenafil should not cause an erection. Vardenafil should not be used in men for whom sexual activity is not recommended due to their underlying cardiovascular status. There is also a risk of developing prolonged erections that last longer than 4 hours, as well as priapism. In the event of a sudden loss of vision in one or both eyes, patients should stop using vardenafil. Patients taking PDE5 inhibitors, such as vardenafil, may also develop sudden hearing loss and experience a prolonged QT interval. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vardenafil inhibits cyclic guanosine monophosphate (GMP) specific phosphodiesterase type 5 (PDE5), which is responsible for the degradation of cyclic GMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic GMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The tissue concentration of cyclic GMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs), and the most abundant PDE in the human corpus cavernosum is PDE5. Therefore, the inhibition of PDE5 by vardenafil enhances erectile function by increasing the amount of cyclic GMP. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Over the recommended dose range, vardenafil has a dose-proportional pharmacokinetics profile. In healthy male volunteers given a single oral dose of 20 mg of vardenafil, maximum plasma concentrations were reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state, and 0.00018% of the dose was detected in semen 1.5 hours after dosing. Vardenafil has a bioavailability of approximately 15%. High-fat meals cause a C max reduction of 18%-50%; however, no changes were detected in AUC or T max. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vardenafil has a steady-state volume of distribution of 208 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 95% of vardenafil and its major circulating metabolite is bound to plasma proteins. Their protein binding is reversible and independent of total drug concentrations. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vardenafil is mainly metabolized by CYP3A4 in the liver, although CYP3A5 and CYP2C isoforms also contribute to its metabolism. The major circulating metabolite, M1 (N-desethylvardenafil), results from desethylation at the piperazine moiety of vardenafil, and has a plasma concentration of approximately 26% of that of the parent compound. M1 has a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Vardenafil is excreted as metabolites mainly through feces and urine. Approximately 91-95% of administered oral dose is found in feces, while 2-6% of administered oral dose is found in urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Vardenafil and its primary metabolite (M1) have a terminal half-life of 4-5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Vardenafil has a total body clearance of 56 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Healthy male volunteers given a single dose of 120 mg of vardenafil experienced reversible back pain, myalgia and abnormal vision. Patients given vardenafil once daily over 4 weeks in single doses up to 80 mg and multiple doses up to 40 mg did not present serious adverse side effects. Cases of severe back pain were observed when 40 mg of vardenafil was administered twice daily; however patients did not present muscle or neurological toxicity. In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance as vardenafil is highly bound to plasma proteins and not significantly eliminated in the urine. No carcinogenic effects were detected in rats and mice given vardenafil daily for 24 months. Vardenafil was not mutagenic or clastogenic, and did not have an effect in fertility in male and female rats given up to 100 mg/kg/day for 28 days prior to mating in males, and for 14 days prior to mating and through day 7 of gestation in females. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Levitra, Staxyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vardenafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction. Output: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. The severity of the interaction is minor.

Does Bupropion and Varenicline interact?

•Drug A: Bupropion •Drug B: Varenicline •Severity: MODERATE •Description: The excretion of Varenicline can be decreased when combined with Bupropion. •Extended Description: Findings from in vitro studies showed that bupropion and its metabolites inhibit OCT2, suggesting that clinically relevant interaction through inhibition of OCT2 could occur at therapeutic bupropion doses. Co-administration of bupropion with OCT2 substrates may result in attenuated OCT2-mediated efflux of those drugs, thereby increasing drug serum concentrations. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For use as an aid in smoking cessation. Varenicline as a nasal spray is indicated for the symptomatic treatment of dry eye disease. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Varenicline is a partial nicotinic acetylcholine receptor agonist, designed to partially activate this system while displacing nicotine at its sites of action in the brain. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Varenicline is an alpha-4 beta-2 neuronal nicotinic acetylcholine receptor partial agonist. The drug shows high selectivity for this receptor subclass, relative to other nicotinic receptors (>500-fold alpha-3 beta-4, >3500-fold alpha-7, >20,000-fold alpha-1 beta gamma delta) or non-nicotinic receptors and transporters (>2000-fold). The drug competitively inhibits the ability of nicotine to bind to and activate the alpha-4 beta-2 receptor. The drug exerts mild agonistic activity at this site, though at a level much lower than nicotine; it is presumed that this activation eases withdrawal symptoms. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Less than 20%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Metabolism is limited (<10%). Most of the active compound is excreted by the kidneys (81%). A minor amount of varenicline is glucuronidated, oxidated, N-formylated, as well as conjugated to form a hexose. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life of varenicline is approximately 24 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Champix, Chantix, Tyrvaya •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Varenicline is a partial agonist at nicotinic acetylcholine receptors used as an aid in smoking cessation.

Findings from in vitro studies showed that bupropion and its metabolites inhibit OCT2, suggesting that clinically relevant interaction through inhibition of OCT2 could occur at therapeutic bupropion doses. Co-administration of bupropion with OCT2 substrates may result in attenuated OCT2-mediated efflux of those drugs, thereby increasing drug serum concentrations. The severity of the interaction is moderate.

Question: Does Bupropion and Varenicline interact? Information: •Drug A: Bupropion •Drug B: Varenicline •Severity: MODERATE •Description: The excretion of Varenicline can be decreased when combined with Bupropion. •Extended Description: Findings from in vitro studies showed that bupropion and its metabolites inhibit OCT2, suggesting that clinically relevant interaction through inhibition of OCT2 could occur at therapeutic bupropion doses. Co-administration of bupropion with OCT2 substrates may result in attenuated OCT2-mediated efflux of those drugs, thereby increasing drug serum concentrations. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For use as an aid in smoking cessation. Varenicline as a nasal spray is indicated for the symptomatic treatment of dry eye disease. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Varenicline is a partial nicotinic acetylcholine receptor agonist, designed to partially activate this system while displacing nicotine at its sites of action in the brain. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Varenicline is an alpha-4 beta-2 neuronal nicotinic acetylcholine receptor partial agonist. The drug shows high selectivity for this receptor subclass, relative to other nicotinic receptors (>500-fold alpha-3 beta-4, >3500-fold alpha-7, >20,000-fold alpha-1 beta gamma delta) or non-nicotinic receptors and transporters (>2000-fold). The drug competitively inhibits the ability of nicotine to bind to and activate the alpha-4 beta-2 receptor. The drug exerts mild agonistic activity at this site, though at a level much lower than nicotine; it is presumed that this activation eases withdrawal symptoms. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Less than 20%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Metabolism is limited (<10%). Most of the active compound is excreted by the kidneys (81%). A minor amount of varenicline is glucuronidated, oxidated, N-formylated, as well as conjugated to form a hexose. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life of varenicline is approximately 24 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Champix, Chantix, Tyrvaya •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Varenicline is a partial agonist at nicotinic acetylcholine receptors used as an aid in smoking cessation. Output: Findings from in vitro studies showed that bupropion and its metabolites inhibit OCT2, suggesting that clinically relevant interaction through inhibition of OCT2 could occur at therapeutic bupropion doses. Co-administration of bupropion with OCT2 substrates may result in attenuated OCT2-mediated efflux of those drugs, thereby increasing drug serum concentrations. The severity of the interaction is moderate.

Does Bupropion and Vecuronium interact?

•Drug A: Bupropion •Drug B: Vecuronium •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Bupropion is combined with Vecuronium. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vecuronium is a muscle relaxing agent and is used as an adjunct in general anesthesia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): The principal pharmacologic effects demonstrated by vecuronium revolve around its competitive binding of cholinergic receptors located at motor end plates. This competitive binding results in muscle relaxant effects that are typically employed as an adjunct to general anesthesia. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vecuronium is a bisquaternary nitrogen compound that acts by competitively binding to nicotinic cholinergic receptors. The binding of vecuronium decreases the opportunity for acetylcholine to bind to the nicotinic receptor at the postjunctional membrane of the myoneural junction. As a result, depolarization is prevented, calcium ions are not released and muscle contraction does not occur. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): 100% •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Fecal (40-75%) and renal (30% as unchanged drug and metabolites) •Half-life (Drug A): 24 hours •Half-life (Drug B): 51–80 minutes •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Vecuronio •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vecuronium is a nondepolarizing neuromuscular blocking agent used to relax muscles or as an adjunct in general anesthesia during surgical procedures.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Vecuronium interact? Information: •Drug A: Bupropion •Drug B: Vecuronium •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Bupropion is combined with Vecuronium. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vecuronium is a muscle relaxing agent and is used as an adjunct in general anesthesia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): The principal pharmacologic effects demonstrated by vecuronium revolve around its competitive binding of cholinergic receptors located at motor end plates. This competitive binding results in muscle relaxant effects that are typically employed as an adjunct to general anesthesia. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vecuronium is a bisquaternary nitrogen compound that acts by competitively binding to nicotinic cholinergic receptors. The binding of vecuronium decreases the opportunity for acetylcholine to bind to the nicotinic receptor at the postjunctional membrane of the myoneural junction. As a result, depolarization is prevented, calcium ions are not released and muscle contraction does not occur. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): 100% •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Fecal (40-75%) and renal (30% as unchanged drug and metabolites) •Half-life (Drug A): 24 hours •Half-life (Drug B): 51–80 minutes •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Vecuronio •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vecuronium is a nondepolarizing neuromuscular blocking agent used to relax muscles or as an adjunct in general anesthesia during surgical procedures. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Vemurafenib interact?

•Drug A: Bupropion •Drug B: Vemurafenib •Severity: MODERATE •Description: The metabolism of Bupropion can be decreased when combined with Vemurafenib. •Extended Description: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vemurafenib is approved since 2011 for the treatment of metastatic melanoma with a mutation on BRAF in the valine located in the exon 15 at codon 600, this mutation is denominated as V600E. The V600E mutation, a substitution of glutamic acid for valine, accounts for 54% of the cases of cutaneous melanoma. Vemurafenib approval was extended in 2017, for its use as a treatment of adult patients with Erdheim-Chester Disease whose cancer cells present BRAF V600 mutation. Erdheim-Chester disease is an extremely rare histiocyte cell disorder that affects large bones, large vessels, central nervous system, as well as, skin and lungs. It is reported an association of Erdheim-Chester disease and V600E mutation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): BRAF activation results in cell growth, proliferation, and metastasis. BRAF is an intermediary molecule in MAPK whose activation depends on ERK activation, elevation of cyclin D1 and cellular proliferation. The mutation V600E produces a constitutively form of BRAF. Vemurafenib has been shown to reduce all activation markers related to BRAF; in clinical trials, vemurafenib treatment showed a reduction of cytoplasmic phosphorylated ERK and a cell proliferation driven by Ki-67. Studies also reported decrease in MAPK-related metabolic activity. All the different reports indicate thet Vemurafenib generates an almost complete inhibition of the MAPK pathway. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vemurafenib is an orally available inhibitor of mutated BRAF-serine-threonine kinase. Vemurafenif is a small molecule that interacts as a competitive inhibitor of the mutated species of BRAF. It is especially potent against the BRAF V600E mutation. Vemurafenib blocks downstream processes to inhibit tumour growth and eventually trigger apoptosis. Vemurafenib does not have antitumour effects against melanoma cell lines with the wild-type BRAF mutation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Vemurafenib is well absorbed after oral administration. Peak concentrations are reached in 3 hours when an oral dose of 960 mg twice daily for 15 days has been given to patients. In the same conditions, Vemurafenib presents a Cmax of 62 mcg/ml and AUC of 601 mcg h/ml. It is unknown how food affects the absorption of vemurafenib. It presents an accumulation ratio of 7.36 after repeating doses of 960 mg •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The estimation of the volume of distribution for Vemurafenib is 106 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Vemurafenib highly binds to plasma proteins where >99% of the administered dose will be found protein bound to serum albumin and alpha-1 acid glycoprotein. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vemurafenib is metabolized by CYP3A4 and the metabolites make up 5% of the components in plasma. The parent compound makes up for the remaining 95%. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Analysis showed that 94% of administered Vemurafenib is excreted via feces and 1% is excreted by urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life of Vemurafenib is estimated to be 57 hours (range of 30-120 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): The total body clearance is 31 L/day. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): In the few toxicity reports, it has been shown an increased in the development of cutaneous squamous cell carcinomas or acceleration in pre-existant tumor growth. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zelboraf •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vemurafenib is a kinase inhibitor used to treat patients with Erdheim-Chester Disease who have the BRAF V600 mutation, and melanoma in patients who have the BRAF V600E mutation.

The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is moderate.

Question: Does Bupropion and Vemurafenib interact? Information: •Drug A: Bupropion •Drug B: Vemurafenib •Severity: MODERATE •Description: The metabolism of Bupropion can be decreased when combined with Vemurafenib. •Extended Description: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vemurafenib is approved since 2011 for the treatment of metastatic melanoma with a mutation on BRAF in the valine located in the exon 15 at codon 600, this mutation is denominated as V600E. The V600E mutation, a substitution of glutamic acid for valine, accounts for 54% of the cases of cutaneous melanoma. Vemurafenib approval was extended in 2017, for its use as a treatment of adult patients with Erdheim-Chester Disease whose cancer cells present BRAF V600 mutation. Erdheim-Chester disease is an extremely rare histiocyte cell disorder that affects large bones, large vessels, central nervous system, as well as, skin and lungs. It is reported an association of Erdheim-Chester disease and V600E mutation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): BRAF activation results in cell growth, proliferation, and metastasis. BRAF is an intermediary molecule in MAPK whose activation depends on ERK activation, elevation of cyclin D1 and cellular proliferation. The mutation V600E produces a constitutively form of BRAF. Vemurafenib has been shown to reduce all activation markers related to BRAF; in clinical trials, vemurafenib treatment showed a reduction of cytoplasmic phosphorylated ERK and a cell proliferation driven by Ki-67. Studies also reported decrease in MAPK-related metabolic activity. All the different reports indicate thet Vemurafenib generates an almost complete inhibition of the MAPK pathway. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vemurafenib is an orally available inhibitor of mutated BRAF-serine-threonine kinase. Vemurafenif is a small molecule that interacts as a competitive inhibitor of the mutated species of BRAF. It is especially potent against the BRAF V600E mutation. Vemurafenib blocks downstream processes to inhibit tumour growth and eventually trigger apoptosis. Vemurafenib does not have antitumour effects against melanoma cell lines with the wild-type BRAF mutation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Vemurafenib is well absorbed after oral administration. Peak concentrations are reached in 3 hours when an oral dose of 960 mg twice daily for 15 days has been given to patients. In the same conditions, Vemurafenib presents a Cmax of 62 mcg/ml and AUC of 601 mcg h/ml. It is unknown how food affects the absorption of vemurafenib. It presents an accumulation ratio of 7.36 after repeating doses of 960 mg •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The estimation of the volume of distribution for Vemurafenib is 106 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Vemurafenib highly binds to plasma proteins where >99% of the administered dose will be found protein bound to serum albumin and alpha-1 acid glycoprotein. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vemurafenib is metabolized by CYP3A4 and the metabolites make up 5% of the components in plasma. The parent compound makes up for the remaining 95%. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Analysis showed that 94% of administered Vemurafenib is excreted via feces and 1% is excreted by urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): The elimination half-life of Vemurafenib is estimated to be 57 hours (range of 30-120 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): The total body clearance is 31 L/day. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): In the few toxicity reports, it has been shown an increased in the development of cutaneous squamous cell carcinomas or acceleration in pre-existant tumor growth. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zelboraf •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vemurafenib is a kinase inhibitor used to treat patients with Erdheim-Chester Disease who have the BRAF V600 mutation, and melanoma in patients who have the BRAF V600E mutation. Output: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is moderate.

Does Bupropion and Venlafaxine interact?

•Drug A: Bupropion •Drug B: Venlafaxine •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Venlafaxine. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Venlafaxine is indicated for the management of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Venlafaxine is an antidepressant agent that works to ameliorate the symptoms of various psychiatric disorders by increasing the level of neurotransmitters in the synapse. Venlafaxine does not mediate muscarinic, histaminergic, or adrenergic effects. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The exact mechanism of action of venlafaxine in the treatment of various psychiatric conditions has not been fully elucidated; however, it is understood that venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) potently and selectively inhibits the reuptake of both serotonin and norepinephrine at the presynaptic terminal. This results in increased levels of neurotransmitters available at the synapse that can stimulate postsynaptic receptors. It is suggested that venlafaxine has a 30-fold selectivity for serotonin compared to norepinephrine: venlafaxine initially inhibits serotonin reuptake at low doses, and with higher doses, it inhibits norepinephrine reuptake in addition to serotonin. Venlafaxine and ODV are also weak inhibitors of dopamine reuptake. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Venlafaxine is well absorbed after oral administration with an absolute bioavailability of approximately 45%. In mass balance studies, at least 92% of a single oral dose of venlafaxine was absorbed. After twice-daily oral administration of immediate-release formulation of 150 mg venlafaxine, C max was 150 ng/mL and T max was 5.5 hours. C max and T max of ODV were 260 ng/mL and nine hours, respectively. The extended-release formulation of venlafaxine has a slower rate of absorption, but the same extent of absorption as the immediate-release formulation. After once-daily administration of extended-release formulation of 75 mg venlafaxine, C max was 225 ng/mL and T max was two hours. C max and T max of ODV were 290 ng/mL and three hours, respectively. Food does not affect the bioavailability of venlafaxine or its active metabolite, O-desmethylvenlafaxine (ODV). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Venlafaxine and ODV is 27% and 30% bound to plasma proteins, respectively. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. It primarily undergoes CYP2D6-mediated demethylation to form its active metabolite O-desmethylvenlafaxine (ODV). Venlafaxine can also undergo N-demethylation mediated by CYP2C9, and CYP2C19, and CYP3A4 to form N-desmethylvenlafaxine (NDV) but this is a minor metabolic pathway. ODV and NDV further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to form N,O-didesmethylvenlafaxine (NODV) and NODV can be further metabolized to form N, N, O-tridesmethylvenlafaxine, followed by a possible glucuronidation. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). •Half-life (Drug A): 24 hours •Half-life (Drug B): The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV. •Clearance (Drug A): No clearance available •Clearance (Drug B): Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral LD 50 was 350 mg/kg in female rats and 700 mg/kg in male rats. There are reports of acute overdosage with venlafaxine either alone or in combination with other drugs including alcohol. Doses up to several-fold higher than the usual therapeutic dose have been ingested in these cases of acute overdosage. Somnolence is the most commonly reported symptom, along with other symptoms such as paresthesia of the extremities, moderate dizziness, altered consciousness, nausea, vomiting, numb hands and feet, hot-cold spells (which occur a few days after the overdose event), hypotension, convulsions, sinus and ventricular tachycardia, rhabdomyolysis, vertigo, liver necrosis, electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), serotonin syndrome, and death. There is no known antidote for venlafaxine overdose. Cases of overdose have been managed with or without symptomatic treatment, hospitalization, and activated charcoal. Retrospective studies suggest that the risk of fatal outcomes from venlafaxine overdosage is higher than that of SSRI antidepressants, but lower than that of tricyclic antidepressants. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Effexor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Venlafaxine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for the treatment of major depression, generalized or social anxiety disorder, and panic disorder.

Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Question: Does Bupropion and Venlafaxine interact? Information: •Drug A: Bupropion •Drug B: Venlafaxine •Severity: MODERATE •Description: The risk or severity of seizure can be increased when Bupropion is combined with Venlafaxine. •Extended Description: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Venlafaxine is indicated for the management of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Venlafaxine is an antidepressant agent that works to ameliorate the symptoms of various psychiatric disorders by increasing the level of neurotransmitters in the synapse. Venlafaxine does not mediate muscarinic, histaminergic, or adrenergic effects. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The exact mechanism of action of venlafaxine in the treatment of various psychiatric conditions has not been fully elucidated; however, it is understood that venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) potently and selectively inhibits the reuptake of both serotonin and norepinephrine at the presynaptic terminal. This results in increased levels of neurotransmitters available at the synapse that can stimulate postsynaptic receptors. It is suggested that venlafaxine has a 30-fold selectivity for serotonin compared to norepinephrine: venlafaxine initially inhibits serotonin reuptake at low doses, and with higher doses, it inhibits norepinephrine reuptake in addition to serotonin. Venlafaxine and ODV are also weak inhibitors of dopamine reuptake. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Venlafaxine is well absorbed after oral administration with an absolute bioavailability of approximately 45%. In mass balance studies, at least 92% of a single oral dose of venlafaxine was absorbed. After twice-daily oral administration of immediate-release formulation of 150 mg venlafaxine, C max was 150 ng/mL and T max was 5.5 hours. C max and T max of ODV were 260 ng/mL and nine hours, respectively. The extended-release formulation of venlafaxine has a slower rate of absorption, but the same extent of absorption as the immediate-release formulation. After once-daily administration of extended-release formulation of 75 mg venlafaxine, C max was 225 ng/mL and T max was two hours. C max and T max of ODV were 290 ng/mL and three hours, respectively. Food does not affect the bioavailability of venlafaxine or its active metabolite, O-desmethylvenlafaxine (ODV). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Venlafaxine and ODV is 27% and 30% bound to plasma proteins, respectively. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. It primarily undergoes CYP2D6-mediated demethylation to form its active metabolite O-desmethylvenlafaxine (ODV). Venlafaxine can also undergo N-demethylation mediated by CYP2C9, and CYP2C19, and CYP3A4 to form N-desmethylvenlafaxine (NDV) but this is a minor metabolic pathway. ODV and NDV further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to form N,O-didesmethylvenlafaxine (NODV) and NODV can be further metabolized to form N, N, O-tridesmethylvenlafaxine, followed by a possible glucuronidation. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). •Half-life (Drug A): 24 hours •Half-life (Drug B): The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV. •Clearance (Drug A): No clearance available •Clearance (Drug B): Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral LD 50 was 350 mg/kg in female rats and 700 mg/kg in male rats. There are reports of acute overdosage with venlafaxine either alone or in combination with other drugs including alcohol. Doses up to several-fold higher than the usual therapeutic dose have been ingested in these cases of acute overdosage. Somnolence is the most commonly reported symptom, along with other symptoms such as paresthesia of the extremities, moderate dizziness, altered consciousness, nausea, vomiting, numb hands and feet, hot-cold spells (which occur a few days after the overdose event), hypotension, convulsions, sinus and ventricular tachycardia, rhabdomyolysis, vertigo, liver necrosis, electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), serotonin syndrome, and death. There is no known antidote for venlafaxine overdose. Cases of overdose have been managed with or without symptomatic treatment, hospitalization, and activated charcoal. Retrospective studies suggest that the risk of fatal outcomes from venlafaxine overdosage is higher than that of SSRI antidepressants, but lower than that of tricyclic antidepressants. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Effexor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Venlafaxine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for the treatment of major depression, generalized or social anxiety disorder, and panic disorder. Output: Bupropion carries a dose-dependent risk of seizure1 that may be further exacerbated when combined with other medications that can reduce the seizure threshold (i.e. increase the risk of seizure), such as the affected drug. This risk may be also compounded by patient-specific factors that may increase the risk of seizure such as metabolic disorders and illicit drug use. The severity of the interaction is moderate.

Does Bupropion and Verapamil interact?

•Drug A: Bupropion •Drug B: Verapamil •Severity: MINOR •Description: Verapamil may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Verapamil is indicated in the treatment of vasopastic (i.e. Prinzmetal's) angina, unstable angina, and chronic stable angina. It is also indicated to treat hypertension, for the prophylaxis of repetitive paroxysmal supraventricular tachycardia, and in combination with digoxin to control ventricular rate in patients with atrial fibrillation or atrial flutter. Given intravenously, it is indicated for the treatment of various supraventricular tachyarrhythmias, including rapid conversion to sinus rhythm in patients with supraventricular tachycardia and for temporary control of ventricular rate in patients with atrial fibrillation or atrial flutter. Verapamil is commonly used off-label for prophylaxis of cluster headaches. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive activity. Immediate-release verapamil has a relatively short duration of action, requiring dosing 3 to 4 times daily, but extended-release formulations are available that allow for once-daily dosing. As verapamil is a negative inotropic medication (i.e. it decreases the strength of myocardial contraction), it should not be used in patients with severe left ventricular dysfunction or hypertrophic cardiomyopathy as the decrease in contractility caused by verapamil may increase the risk of exacerbating these pre-existing conditions. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Verapamil inhibits L-type calcium channels by binding to a specific area of their alpha-1 subunit, Cav1.2, which is highly expressed on L-type calcium channels in vascular smooth muscle and myocardial tissue where these channels are responsible for the control of peripheral vascular resistance and heart contractility. Calcium influx through these channels allows for the propagation of action potentials necessary for the contraction of muscle tissue and the heart's electrical pacemaker activity. Verapamil binds to these channels in a voltage- and frequency-dependent manner, meaning affinity is increased 1) as vascular smooth muscle membrane potential is reduced, and 2) with excessive depolarizing stimulus. Verapamil's mechanism of action in the treatment of angina and hypertension is likely due to the mechanism described above. Inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation - this lowers systemic vascular resistance (i.e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina. Electrical activity through the AV node is responsible for determining heart rate, and this activity is dependent upon calcium influx through L-type calcium channels. By inhibiting these channels and decreasing the influx of calcium, verapamil prolongs the refractory period of the AV node and slows conduction, thereby slowing and controlling the heart rate in patients with arrhythmia. Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to result from an effect on other calcium channels (e.g. N-, P-, Q-, or T-type). Verapamil is known to interact with other targets, including other calcium channels, potassium channels, and adrenergic receptors. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): More than 90% of orally administered verapamil is absorbed - despite this, bioavailability ranges only from 20% to 30% due to rapid biotransformation following first-pass metabolism in the portal circulation. Absorption kinetic parameters are largely dependent on the specific formulation of verapamil involved. Immediate-release verapamil reaches peak plasma concentrations (i.e. T max ) between 1-2 hours following administration, whereas sustained-release formulations tend to have a T max between 6 - 11 hours. AUC and C max values are similarly dependent upon formulation. Chronic administration of immediate-release verapamil every 6 hours resulted in plasma concentrations between 125 and 400 ng/mL. Steady-state AUC 0-24h and C max values for a sustained-release formulation were 1037 ng∙h/ml and 77.8 ng/mL for the R-isomer and 195 ng∙h/ml and 16.8 ng/mL for the S-isomer, respectively. Interestingly, the absorption kinetics of verapamil are highly stereospecific - following oral administration of immediate-release verapamil every 8 hours, the relative systemic availability of the S-enantiomer compared to the R-enantiomer was 13% after a single dose and 18% at steady-state. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Verapamil has a steady-state volume of distribution of approximately 300L for its R-enantiomer and 500L for its S-enantiomer. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Verapamil is extensively protein-bound in plasma. R-verapamil is 94% bound to serum albumin while S-verapamil is 88% bound. Additionally, R-verapamil is 92% bound to alpha-1 acid glycoprotein and S-verapamil is 86% bound. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Verapamil is extensively metabolized by the liver, with up to 80% of an administered dose subject to elimination via pre-systemic metabolism - interestingly, this first-pass metabolism appears to clear the S-enantiomer of verapamil much faster than the R-enantiomer. The remaining parent drug undergoes O-demethylation, N-dealkylation, and N-demethylation to a number of different metabolites via the cytochrome P450 enzyme system. Norverapamil, one of the major circulating metabolites, is the result of verapamil's N-demethylation via CYP2C8, CYP3A4, and CYP3A5, and carries approximately 20% of the cardiovascular activity of its parent drug. The other major pathway involved in verapamil metabolism is N-dealkylation via CYP2C8, CYP3A4, and CYP1A2 to the D-617 metabolite. Both norverapamil and D-617 are further metabolized by other CYP isoenzymes to various secondary metabolites. CYP2D6 and CYP2E1 have also been implicated in the metabolic pathway of verapamil, albeit to a minor extent. Minor pathways of verapamil metabolism involve its O-demethylation to D-703 via CYP2C8, CYP2C9, and CYP2C18, and to D-702 via CYP2C9 and CYP2C18. Several steps in verapamil's metabolic pathway show stereoselective preference for the S-enantiomer of the given substrate, including the generation of the D-620 metabolite by CYP3A4/5 and the D-617 metabolite by CYP2C8. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 70% of an administered dose is excreted as metabolites in the urine and ≥16% in the feces within 5 days. Approximately 3% - 4% is excreted in the urine as unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): Single-dose studies of immediate-release verapamil have demonstrated an elimination half-life of 2.8 to 7.4 hours, which increases to 4.5 to 12.0 hours following repetitive dosing. The elimination half-life is also prolonged in patients with hepatic insufficiency (14 to 16 hours) and in the elderly (approximately 20 hours). Intravenously administered verapamil has rapid distribution phase half-life of approximately 4 minutes, followed by a terminal elimination phase half-life of 2 to 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Systemic clearance following 3 weeks of continuous treatment was approximately 340 mL/min for R-verapamil and 664 mL/min for S-verapamil. Of note, apparent oral clearance appears to vary significantly between single dose and multiple-dose conditions. The apparent oral clearance following single doses of verapamil was approximately 1007 mL/min for R-verapamil and 5481 mL/min for S-verapamil, whereas 3 weeks of continuous treatment resulted in apparent oral clearance values of approximately 651 mL/min for R-verapamil and 2855 mL/min for S-verapamil. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Verapamil's reported oral TDLo is 14.4 mg/kg in women and 3.429 mg/kg in men. The oral LD 50 is 150 mg/kg in rats and 163 mg/kg in mice. As there is no antidote for verapamil overdosage, treatment is largely supportive. Symptoms of overdose are generally consistent with verapamil's adverse effect profile (i.e. hypotension, bradycardia, arrhythmia) but instances of non-cardiogenic pulmonary edema have been observed following ingestion of large overdoses (up to 9 grams). In acute overdosage, consider the use of gastrointestinal decontamination with cathartics and/or bowel irrigation. Patients presenting with significant myocardial depression may require intravenous calcium, atropine, vasopressors, or other inotropes. Consider the formulation responsible for the overdose prior to treatment - sustained-release formulations may result in delayed pharmacodynamic effects, and these patients should be monitored closely for at least 48 hours following ingestion. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Calan, Isoptin, Tarka, Verelan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Verapamil is a non-dihydropyridine calcium channel blocker used in the treatment of angina, arrhythmia, and hypertension.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Verapamil interact? Information: •Drug A: Bupropion •Drug B: Verapamil •Severity: MINOR •Description: Verapamil may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Verapamil is indicated in the treatment of vasopastic (i.e. Prinzmetal's) angina, unstable angina, and chronic stable angina. It is also indicated to treat hypertension, for the prophylaxis of repetitive paroxysmal supraventricular tachycardia, and in combination with digoxin to control ventricular rate in patients with atrial fibrillation or atrial flutter. Given intravenously, it is indicated for the treatment of various supraventricular tachyarrhythmias, including rapid conversion to sinus rhythm in patients with supraventricular tachycardia and for temporary control of ventricular rate in patients with atrial fibrillation or atrial flutter. Verapamil is commonly used off-label for prophylaxis of cluster headaches. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive activity. Immediate-release verapamil has a relatively short duration of action, requiring dosing 3 to 4 times daily, but extended-release formulations are available that allow for once-daily dosing. As verapamil is a negative inotropic medication (i.e. it decreases the strength of myocardial contraction), it should not be used in patients with severe left ventricular dysfunction or hypertrophic cardiomyopathy as the decrease in contractility caused by verapamil may increase the risk of exacerbating these pre-existing conditions. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Verapamil inhibits L-type calcium channels by binding to a specific area of their alpha-1 subunit, Cav1.2, which is highly expressed on L-type calcium channels in vascular smooth muscle and myocardial tissue where these channels are responsible for the control of peripheral vascular resistance and heart contractility. Calcium influx through these channels allows for the propagation of action potentials necessary for the contraction of muscle tissue and the heart's electrical pacemaker activity. Verapamil binds to these channels in a voltage- and frequency-dependent manner, meaning affinity is increased 1) as vascular smooth muscle membrane potential is reduced, and 2) with excessive depolarizing stimulus. Verapamil's mechanism of action in the treatment of angina and hypertension is likely due to the mechanism described above. Inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation - this lowers systemic vascular resistance (i.e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina. Electrical activity through the AV node is responsible for determining heart rate, and this activity is dependent upon calcium influx through L-type calcium channels. By inhibiting these channels and decreasing the influx of calcium, verapamil prolongs the refractory period of the AV node and slows conduction, thereby slowing and controlling the heart rate in patients with arrhythmia. Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to result from an effect on other calcium channels (e.g. N-, P-, Q-, or T-type). Verapamil is known to interact with other targets, including other calcium channels, potassium channels, and adrenergic receptors. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): More than 90% of orally administered verapamil is absorbed - despite this, bioavailability ranges only from 20% to 30% due to rapid biotransformation following first-pass metabolism in the portal circulation. Absorption kinetic parameters are largely dependent on the specific formulation of verapamil involved. Immediate-release verapamil reaches peak plasma concentrations (i.e. T max ) between 1-2 hours following administration, whereas sustained-release formulations tend to have a T max between 6 - 11 hours. AUC and C max values are similarly dependent upon formulation. Chronic administration of immediate-release verapamil every 6 hours resulted in plasma concentrations between 125 and 400 ng/mL. Steady-state AUC 0-24h and C max values for a sustained-release formulation were 1037 ng∙h/ml and 77.8 ng/mL for the R-isomer and 195 ng∙h/ml and 16.8 ng/mL for the S-isomer, respectively. Interestingly, the absorption kinetics of verapamil are highly stereospecific - following oral administration of immediate-release verapamil every 8 hours, the relative systemic availability of the S-enantiomer compared to the R-enantiomer was 13% after a single dose and 18% at steady-state. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Verapamil has a steady-state volume of distribution of approximately 300L for its R-enantiomer and 500L for its S-enantiomer. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Verapamil is extensively protein-bound in plasma. R-verapamil is 94% bound to serum albumin while S-verapamil is 88% bound. Additionally, R-verapamil is 92% bound to alpha-1 acid glycoprotein and S-verapamil is 86% bound. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Verapamil is extensively metabolized by the liver, with up to 80% of an administered dose subject to elimination via pre-systemic metabolism - interestingly, this first-pass metabolism appears to clear the S-enantiomer of verapamil much faster than the R-enantiomer. The remaining parent drug undergoes O-demethylation, N-dealkylation, and N-demethylation to a number of different metabolites via the cytochrome P450 enzyme system. Norverapamil, one of the major circulating metabolites, is the result of verapamil's N-demethylation via CYP2C8, CYP3A4, and CYP3A5, and carries approximately 20% of the cardiovascular activity of its parent drug. The other major pathway involved in verapamil metabolism is N-dealkylation via CYP2C8, CYP3A4, and CYP1A2 to the D-617 metabolite. Both norverapamil and D-617 are further metabolized by other CYP isoenzymes to various secondary metabolites. CYP2D6 and CYP2E1 have also been implicated in the metabolic pathway of verapamil, albeit to a minor extent. Minor pathways of verapamil metabolism involve its O-demethylation to D-703 via CYP2C8, CYP2C9, and CYP2C18, and to D-702 via CYP2C9 and CYP2C18. Several steps in verapamil's metabolic pathway show stereoselective preference for the S-enantiomer of the given substrate, including the generation of the D-620 metabolite by CYP3A4/5 and the D-617 metabolite by CYP2C8. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 70% of an administered dose is excreted as metabolites in the urine and ≥16% in the feces within 5 days. Approximately 3% - 4% is excreted in the urine as unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): Single-dose studies of immediate-release verapamil have demonstrated an elimination half-life of 2.8 to 7.4 hours, which increases to 4.5 to 12.0 hours following repetitive dosing. The elimination half-life is also prolonged in patients with hepatic insufficiency (14 to 16 hours) and in the elderly (approximately 20 hours). Intravenously administered verapamil has rapid distribution phase half-life of approximately 4 minutes, followed by a terminal elimination phase half-life of 2 to 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Systemic clearance following 3 weeks of continuous treatment was approximately 340 mL/min for R-verapamil and 664 mL/min for S-verapamil. Of note, apparent oral clearance appears to vary significantly between single dose and multiple-dose conditions. The apparent oral clearance following single doses of verapamil was approximately 1007 mL/min for R-verapamil and 5481 mL/min for S-verapamil, whereas 3 weeks of continuous treatment resulted in apparent oral clearance values of approximately 651 mL/min for R-verapamil and 2855 mL/min for S-verapamil. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Verapamil's reported oral TDLo is 14.4 mg/kg in women and 3.429 mg/kg in men. The oral LD 50 is 150 mg/kg in rats and 163 mg/kg in mice. As there is no antidote for verapamil overdosage, treatment is largely supportive. Symptoms of overdose are generally consistent with verapamil's adverse effect profile (i.e. hypotension, bradycardia, arrhythmia) but instances of non-cardiogenic pulmonary edema have been observed following ingestion of large overdoses (up to 9 grams). In acute overdosage, consider the use of gastrointestinal decontamination with cathartics and/or bowel irrigation. Patients presenting with significant myocardial depression may require intravenous calcium, atropine, vasopressors, or other inotropes. Consider the formulation responsible for the overdose prior to treatment - sustained-release formulations may result in delayed pharmacodynamic effects, and these patients should be monitored closely for at least 48 hours following ingestion. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Calan, Isoptin, Tarka, Verelan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Verapamil is a non-dihydropyridine calcium channel blocker used in the treatment of angina, arrhythmia, and hypertension. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Vernakalant interact?

•Drug A: Bupropion •Drug B: Vernakalant •Severity: MAJOR •Description: The metabolism of Vernakalant can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated for the rapid conversion of recent onset of atrial fibrillation to sinus rhythm in adults for non-surgery patients that lasts for less than 7 days of duration and post-cardiac surgery patients with atrial fibrillation lasting less than 3 days of duration. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vernakalant blocks currents in all phases of atrial action potential including atria-specific potassium currents (the ultra-rapid delayed rectifier and the acetylcholine dependent potassium currents) and prolongs the refractory period. It dose-dependently prolongs atrial refractoriness, prolongs AV nodal conduction and refractoriness, and slightly prolongs QRS duration without significantly affecting ventricular refractory period. Vernakalant has a high affinity to ion channels specifically involved in repolarization of atrial tissue and is thought to have a low proarrhythmic potential. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vernakalant blocks atrial voltage-gated sodium channels in a dose and frequency-dependent manner and inhibits late sodium current (INa)which confers its effect on intra-atrial conduction. This current blockade enhance and onset of drug action accelerates in higher heart rate as the affinity of vernakalant for INa also increases. Its binding offset is quick once the heart rate slows. It also blocks Kv 1.5 channel and its early activating potassium channels (IKur) and inhibits acetylcholine-activated potassium channels (IKAch), which are specific to the atrium and cause prolongation of atrial refractoriness. Vernakalant also blocks Kv4.3 channel and its cardiac transient outward potassium current (Ito), which is involved more with atrial than ventricular refractoriness. Vernakalant minimally blocks hERG channels and its rapidly activating/delayed rectifying potassium current (IKr) which accounts for mild QT prolongation. QRS widening due to INa blockade also contributes to QT prolongation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): In patients, average peak plasma concentrations of vernakalant were 3.9 μg/ml following a single 10 minute infusion of 3 mg/kg vernakalant hydrochloride, and 4.3 μg/ml following a second infusion of 2 mg/kg with a 15 minute interval between doses. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Approximately 2L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Displays low protein binding and the free fraction of vernakalant in human serum is 53-63% at concentration range of 1-5 μg/ml. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vernakalant is mainly eliminated by CYP2D6 mediated O-demethylation in CYP2D6 extensive metabolisers. Glucuronidation is the main metabolism pathway in CYP2D6 poor metabolisers. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Mainly eliminated via renal excretion. •Half-life (Drug A): 24 hours •Half-life (Drug B): Elimination half life in CYP2D6 extensive metabolizers is 3 hours and 5.5 hours in poor metabolizers. •Clearance (Drug A): No clearance available •Clearance (Drug B): The typical total body clearance of vernakalant was estimated to be 0.41 l/hr/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Some common unwanted effects include hypotension, ventricular arrhythmias, bradycardia, atrial flutter, dysgeusia, paraesthesia, dizziness and nausea. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Brinavess •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Vernakalant •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vernakalant is an antiarrhythmic medication used to treat patients with atrial fibrillation.

The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Vernakalant interact? Information: •Drug A: Bupropion •Drug B: Vernakalant •Severity: MAJOR •Description: The metabolism of Vernakalant can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated for the rapid conversion of recent onset of atrial fibrillation to sinus rhythm in adults for non-surgery patients that lasts for less than 7 days of duration and post-cardiac surgery patients with atrial fibrillation lasting less than 3 days of duration. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vernakalant blocks currents in all phases of atrial action potential including atria-specific potassium currents (the ultra-rapid delayed rectifier and the acetylcholine dependent potassium currents) and prolongs the refractory period. It dose-dependently prolongs atrial refractoriness, prolongs AV nodal conduction and refractoriness, and slightly prolongs QRS duration without significantly affecting ventricular refractory period. Vernakalant has a high affinity to ion channels specifically involved in repolarization of atrial tissue and is thought to have a low proarrhythmic potential. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vernakalant blocks atrial voltage-gated sodium channels in a dose and frequency-dependent manner and inhibits late sodium current (INa)which confers its effect on intra-atrial conduction. This current blockade enhance and onset of drug action accelerates in higher heart rate as the affinity of vernakalant for INa also increases. Its binding offset is quick once the heart rate slows. It also blocks Kv 1.5 channel and its early activating potassium channels (IKur) and inhibits acetylcholine-activated potassium channels (IKAch), which are specific to the atrium and cause prolongation of atrial refractoriness. Vernakalant also blocks Kv4.3 channel and its cardiac transient outward potassium current (Ito), which is involved more with atrial than ventricular refractoriness. Vernakalant minimally blocks hERG channels and its rapidly activating/delayed rectifying potassium current (IKr) which accounts for mild QT prolongation. QRS widening due to INa blockade also contributes to QT prolongation. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): In patients, average peak plasma concentrations of vernakalant were 3.9 μg/ml following a single 10 minute infusion of 3 mg/kg vernakalant hydrochloride, and 4.3 μg/ml following a second infusion of 2 mg/kg with a 15 minute interval between doses. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Approximately 2L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Displays low protein binding and the free fraction of vernakalant in human serum is 53-63% at concentration range of 1-5 μg/ml. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vernakalant is mainly eliminated by CYP2D6 mediated O-demethylation in CYP2D6 extensive metabolisers. Glucuronidation is the main metabolism pathway in CYP2D6 poor metabolisers. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Mainly eliminated via renal excretion. •Half-life (Drug A): 24 hours •Half-life (Drug B): Elimination half life in CYP2D6 extensive metabolizers is 3 hours and 5.5 hours in poor metabolizers. •Clearance (Drug A): No clearance available •Clearance (Drug B): The typical total body clearance of vernakalant was estimated to be 0.41 l/hr/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Some common unwanted effects include hypotension, ventricular arrhythmias, bradycardia, atrial flutter, dysgeusia, paraesthesia, dizziness and nausea. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Brinavess •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Vernakalant •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vernakalant is an antiarrhythmic medication used to treat patients with atrial fibrillation. Output: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Vigabatrin interact?

•Drug A: Bupropion •Drug B: Vigabatrin •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Vigabatrin is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vigabatrin is indicated as adjunctive therapy in the treatment of refractory complex partial seizures in patients 2 years of age and older who have had inadequate responses to multiple previous treatments (i.e. not to be used for first-line therapy). It is also indicated as monotherapy in the treatment of infantile spasms in patients between 1 month and 2 years of age for whom the potential benefits outweigh the risk of vision loss. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vigabatrin is an antiepileptic agent chemically unrelated to other anticonvulsants. Vigabatrin prevents the metabolism of GABA by irreversibly inhibiting GABA transaminase (GABA-T). As vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), its duration of effect is thought to be dependent on the rate of GABA-T re-synthesis rather than on the rate of drug elimination. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Gamma-aminobutyric acid (GABA) is the major inhibitory transmitter throughout the central nervous system, and the potentiation of GABAergic neurotransmission is therefore a crucial mechanism through which antiepileptic agents may combat the pathologic excitatory neurotransmission seen in epilepsy. Vigabatrin increases concentrations of GABA in the central nervous system by irreversibly inhibiting the enzymes responsible for its metabolism to succinic semialdehyde: gamma-aminobutyric acid transaminase (GABA-T). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Absorption following oral administration is essentially complete. The T max is approximately 2.5 hours in infants (5m - 2y) and 1 hour in all other age groups. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vigabatrin is widely distributed throughout the body with a mean steady-state volume of distribution of 1.1 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Vigabatrin does not bind to plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vigabatrin is not metabolized to any significant extent. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 95% of the drug is eliminated in the urine within 72 hours of administration, of which ~80% is unchanged parent drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): The terminal half-life of vigabatrin is approximately 5.7 hours for infants (5m - 2y), 6.8 hours for children (3y - 9y), 9.5 hours for adolescents (10y - 16y), and 10.5 h for adults. •Clearance (Drug A): No clearance available •Clearance (Drug B): The oral clearance of vigabatrin is 2.4 L/h for infants (5m - 2y), 5.1 L/h for children (3y - 9y), 5.8 L/h for adolescents (10y - 16y), and 7 L/h for adults. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 of vigabatrin in mice and rats is 2830 mg/kg and 3100 mg/kg, respectively. Symptoms of overdose tend to involve significant CNS depression - e.g. coma, unconsciousness, and/or drowsiness - with less common symptoms including neurologic disorders (e.g. seizure activity, speech disorder, headache) and psychiatric sequelae (e.g. psychosis, agitation, abnormal behaviour, confusion). In cases of overdose, symptoms generally resolve with symptomatic and supportive care. Standard measures to remove unabsorbed drug may be employed (e.g. gastric lavage), although an in vitro study found that activated charcoal did not significantly absorb vigabatrin. Although vigabatrin is not protein-bound, the effectiveness of hemodialysis in drug removal during overdose is unknown - isolated reports of patients in renal failure undergoing hemodialysis who were receiving therapeutic doses of vigabatrin note a reduction in vigabatrin plasma concentrations of 40-60% following dialysis. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Sabril, Vigadrone, Vigpoder •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gamma vinyl GABA gamma-Vinyl GABA Vigabatrin Vigabatrina Vigabatrine Vigabatrinum Vinyl gamma-aminobutyric acid •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vigabatrin is an irreversible GABA transaminase inhibitor used as an adjunct therapy to treat refractory complex partial seizures in patients ≥2 years unresponsive to alternatives. May also be used as monotherapy to treat infantile spasms in infants 1 month to 2 years.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Vigabatrin interact? Information: •Drug A: Bupropion •Drug B: Vigabatrin •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Vigabatrin is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vigabatrin is indicated as adjunctive therapy in the treatment of refractory complex partial seizures in patients 2 years of age and older who have had inadequate responses to multiple previous treatments (i.e. not to be used for first-line therapy). It is also indicated as monotherapy in the treatment of infantile spasms in patients between 1 month and 2 years of age for whom the potential benefits outweigh the risk of vision loss. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vigabatrin is an antiepileptic agent chemically unrelated to other anticonvulsants. Vigabatrin prevents the metabolism of GABA by irreversibly inhibiting GABA transaminase (GABA-T). As vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), its duration of effect is thought to be dependent on the rate of GABA-T re-synthesis rather than on the rate of drug elimination. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Gamma-aminobutyric acid (GABA) is the major inhibitory transmitter throughout the central nervous system, and the potentiation of GABAergic neurotransmission is therefore a crucial mechanism through which antiepileptic agents may combat the pathologic excitatory neurotransmission seen in epilepsy. Vigabatrin increases concentrations of GABA in the central nervous system by irreversibly inhibiting the enzymes responsible for its metabolism to succinic semialdehyde: gamma-aminobutyric acid transaminase (GABA-T). •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Absorption following oral administration is essentially complete. The T max is approximately 2.5 hours in infants (5m - 2y) and 1 hour in all other age groups. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vigabatrin is widely distributed throughout the body with a mean steady-state volume of distribution of 1.1 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Vigabatrin does not bind to plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vigabatrin is not metabolized to any significant extent. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Approximately 95% of the drug is eliminated in the urine within 72 hours of administration, of which ~80% is unchanged parent drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): The terminal half-life of vigabatrin is approximately 5.7 hours for infants (5m - 2y), 6.8 hours for children (3y - 9y), 9.5 hours for adolescents (10y - 16y), and 10.5 h for adults. •Clearance (Drug A): No clearance available •Clearance (Drug B): The oral clearance of vigabatrin is 2.4 L/h for infants (5m - 2y), 5.1 L/h for children (3y - 9y), 5.8 L/h for adolescents (10y - 16y), and 7 L/h for adults. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 of vigabatrin in mice and rats is 2830 mg/kg and 3100 mg/kg, respectively. Symptoms of overdose tend to involve significant CNS depression - e.g. coma, unconsciousness, and/or drowsiness - with less common symptoms including neurologic disorders (e.g. seizure activity, speech disorder, headache) and psychiatric sequelae (e.g. psychosis, agitation, abnormal behaviour, confusion). In cases of overdose, symptoms generally resolve with symptomatic and supportive care. Standard measures to remove unabsorbed drug may be employed (e.g. gastric lavage), although an in vitro study found that activated charcoal did not significantly absorb vigabatrin. Although vigabatrin is not protein-bound, the effectiveness of hemodialysis in drug removal during overdose is unknown - isolated reports of patients in renal failure undergoing hemodialysis who were receiving therapeutic doses of vigabatrin note a reduction in vigabatrin plasma concentrations of 40-60% following dialysis. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Sabril, Vigadrone, Vigpoder •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gamma vinyl GABA gamma-Vinyl GABA Vigabatrin Vigabatrina Vigabatrine Vigabatrinum Vinyl gamma-aminobutyric acid •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vigabatrin is an irreversible GABA transaminase inhibitor used as an adjunct therapy to treat refractory complex partial seizures in patients ≥2 years unresponsive to alternatives. May also be used as monotherapy to treat infantile spasms in infants 1 month to 2 years. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Vilanterol interact?

•Drug A: Bupropion •Drug B: Vilanterol •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Vilanterol which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vilanterol is approved for use in several combination products such as with fluticasone furoate under the tradename Breo Ellipta, in combination with umeclidinium bromide as Anoro Ellipta, and in combination with both fluticasone furoate and umeclidinium under the tradename Trelegy Ellipta. Approved by the FDA in 2013, the use of Breo Ellipta is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema, as well as the once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease. Anoro Ellipta is indicated for the maintenance treatment of patients with COPD, and Trelegy Ellipta is indicated for the maintenance treatment of patients with COPD as well as the maintenance treatment of asthma in patients aged 18 years and older. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vilanterol is a selective long-acting beta2-adrenergic agonist. Its pharmacological effect is attributable to stimulation of intracellular adenylyl cyclase which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cAMP). Increases in cyclic AMP are associated with relaxation of bronchial smooth muscle and inhibition of release of hypersensitivity mediators from mast cells in the lungs. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Vilanterol plasma levels may not predict therapeutic effects. Following inhaled administration of vilanterol in healthy subjects, C max occurred at 5 to 15 minutes. Vilanterol is mostly absorbed from the lung after inhaled doses with negligible contribution from oral absorption. Following repeat dosing of inhaled vilanterol, the steady state was achieved within 14 days with up to 1.7-fold accumulation. The absolute bioavailability of vilanterol when administered by inhalation was 27.3%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose of vilanterol is low (<2%) due to extensive first-pass metabolism. Systemic exposure (AUC) in patients with COPD was 24% higher than observed in healthy subjects. Systemic exposure (AUC) in patients with asthma was 21% lower than observed in healthy subjects. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following intravenous administration to healthy subjects, the mean volume of distribution at steady-state was 165 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): In vitro plasma protein binding in human plasma was on average 94%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vilanterol is principally metabolized by cytochrome p450 3A4 (CYP3A4) to a range of metabolites with significantly reduced beta1- and beta2-agonist activity. The major route of metabolism was via O-dealkylation, with up to 78% of the recovered dose eliminated as O-dealkylated metabolites while N-Dealkylation and C-dealkylation were minor pathways, representing 5% of the recovered dose. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following oral administration of radiolabeled vilanterol, mass balance showed 70% of the radiolabel in the urine and 30% in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): The effective half-life for vilanterol, as determined from inhalation administration of multiple doses, is 11 hours. The plasma elimination half-life, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in patients with COPD and 16.0 hours in patients with asthma. For a single dose inhaled administration, the plasma elimination phase half-life averaged 2.5 hour. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, the pharmacokinetics of vilanterol showed a high plasma clearance of 108 L/hour. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): In separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 450 times, respectively, the maximum recommended human daily inhaled dose (MRHDID) (on an mcg/m2 basis at maternal inhalation doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 5,740 mcg/kg/day in rabbits). No evidence of structural abnormalities was observed at any dose in rats or in rabbits up to approximately 70 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 450 times the MRHDID (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in the cervical vertebral centrum and metacarpals. In a perinatal and postnatal developmental study in rats, dams received vilanterol during late gestation and the lactation periods at doses up to approximately 3,900 times the MRHDID (on an mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects on offspring development was observed. The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest, and even death may be associated with an overdose of vilanterol. In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhaled dose of 29,500 mcg/kg/day (approximately 7,800 times the MRHDID for adults on an AUC basis). No increase in tumors was seen at an inhaled dose of 615 mcg/kg/day (approximately 210 times the MRHDID for adults on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and a shortening of the latency of pituitary tumors at inhaled doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 20 times the MRHDID for adults on an AUC basis). No tumors were seen at an inhaled dose of 10.5 mcg/kg/day (approximately equal to the MRHDID for adults on an AUC basis). These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Anoro, Anoro Ellipta, Breo Ellipta, Trelegy Ellipta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vilanterol is a long-acting beta2-adrenergic agonist used in combination with other bronchodilators for the management of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Vilanterol interact? Information: •Drug A: Bupropion •Drug B: Vilanterol •Severity: MINOR •Description: Bupropion may decrease the excretion rate of Vilanterol which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vilanterol is approved for use in several combination products such as with fluticasone furoate under the tradename Breo Ellipta, in combination with umeclidinium bromide as Anoro Ellipta, and in combination with both fluticasone furoate and umeclidinium under the tradename Trelegy Ellipta. Approved by the FDA in 2013, the use of Breo Ellipta is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema, as well as the once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease. Anoro Ellipta is indicated for the maintenance treatment of patients with COPD, and Trelegy Ellipta is indicated for the maintenance treatment of patients with COPD as well as the maintenance treatment of asthma in patients aged 18 years and older. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vilanterol is a selective long-acting beta2-adrenergic agonist. Its pharmacological effect is attributable to stimulation of intracellular adenylyl cyclase which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cAMP). Increases in cyclic AMP are associated with relaxation of bronchial smooth muscle and inhibition of release of hypersensitivity mediators from mast cells in the lungs. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Vilanterol plasma levels may not predict therapeutic effects. Following inhaled administration of vilanterol in healthy subjects, C max occurred at 5 to 15 minutes. Vilanterol is mostly absorbed from the lung after inhaled doses with negligible contribution from oral absorption. Following repeat dosing of inhaled vilanterol, the steady state was achieved within 14 days with up to 1.7-fold accumulation. The absolute bioavailability of vilanterol when administered by inhalation was 27.3%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose of vilanterol is low (<2%) due to extensive first-pass metabolism. Systemic exposure (AUC) in patients with COPD was 24% higher than observed in healthy subjects. Systemic exposure (AUC) in patients with asthma was 21% lower than observed in healthy subjects. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following intravenous administration to healthy subjects, the mean volume of distribution at steady-state was 165 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): In vitro plasma protein binding in human plasma was on average 94%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vilanterol is principally metabolized by cytochrome p450 3A4 (CYP3A4) to a range of metabolites with significantly reduced beta1- and beta2-agonist activity. The major route of metabolism was via O-dealkylation, with up to 78% of the recovered dose eliminated as O-dealkylated metabolites while N-Dealkylation and C-dealkylation were minor pathways, representing 5% of the recovered dose. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following oral administration of radiolabeled vilanterol, mass balance showed 70% of the radiolabel in the urine and 30% in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): The effective half-life for vilanterol, as determined from inhalation administration of multiple doses, is 11 hours. The plasma elimination half-life, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in patients with COPD and 16.0 hours in patients with asthma. For a single dose inhaled administration, the plasma elimination phase half-life averaged 2.5 hour. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, the pharmacokinetics of vilanterol showed a high plasma clearance of 108 L/hour. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): In separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 450 times, respectively, the maximum recommended human daily inhaled dose (MRHDID) (on an mcg/m2 basis at maternal inhalation doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 5,740 mcg/kg/day in rabbits). No evidence of structural abnormalities was observed at any dose in rats or in rabbits up to approximately 70 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 450 times the MRHDID (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in the cervical vertebral centrum and metacarpals. In a perinatal and postnatal developmental study in rats, dams received vilanterol during late gestation and the lactation periods at doses up to approximately 3,900 times the MRHDID (on an mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects on offspring development was observed. The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest, and even death may be associated with an overdose of vilanterol. In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhaled dose of 29,500 mcg/kg/day (approximately 7,800 times the MRHDID for adults on an AUC basis). No increase in tumors was seen at an inhaled dose of 615 mcg/kg/day (approximately 210 times the MRHDID for adults on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and a shortening of the latency of pituitary tumors at inhaled doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 20 times the MRHDID for adults on an AUC basis). No tumors were seen at an inhaled dose of 10.5 mcg/kg/day (approximately equal to the MRHDID for adults on an AUC basis). These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Anoro, Anoro Ellipta, Breo Ellipta, Trelegy Ellipta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vilanterol is a long-acting beta2-adrenergic agonist used in combination with other bronchodilators for the management of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Vilazodone interact?

•Drug A: Bupropion •Drug B: Vilazodone •Severity: MAJOR •Description: The metabolism of Vilazodone can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vilazodone is approved for treatment of major depressive disorder. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vilazodone increases serotonin levels in the brain by inhibiting the reuptake of serotonin while acting as a partial agonist on serotonin-1A receptors. Due to this activity vilazodone has sometimes been referred to as a selective partial agonist and reuptake inhibitor (SPARI). •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vilazodone selectively inhibits serotonin reuptake in the central nervous system as well as acting as a partial agonist of 5HT-1A receptors. The exact mechanism for how these effects translate to its antidepressant effects are not known, though there is an association between these effects and antidepressive activity. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Vilazodone's bioavailability is 72% when taken with food. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vilazodone's volume of distribution is unknown but large •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 96-99%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vilazodone is mainly metabolized by cytochrome P450(CYP)3A4 and also to a minor extent by CYP2C19 and CYP 2D6. Although the metabolic pathway for vilazodone has not been fully studied, a proposed mechanism for metabolism in rats was published in 2017. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): 1% of the dose is recovered unchanged in the urine and 2% of the dose is recovered unchanged in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): 25 hours. Other studies show a half life of 24±5.2h with a single 40mg dose and 28.9±3.2h with repeated doses. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance of vilazodone is 19.9-25.1L/h in patients with mild to moderate renal impairment compared to 26.4-26.9L/h in healthy controls. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): There is a lack of clinical studies of vilazodone in pregnancy. Animal studies have shown the effects on offspring to be reduced fetal weight, increased mortality, delayed maturation, and decreased fertility in adulthood at doses well above the maximum recommended human dose. Clinical cases of fetal and neonatal exposure to SSRIs and SNRIs have lead to a number of complications including respiratory distress, seizures, and temperature instability. It is not know whether vilazodone is excreted in the breast milk of nursing mothers but animal studies show this is the case for rats. The risk and benefit of breast feeding while taking vilazodone for mother and child must be considered before a decision is made. Safety and effectiveness in pediatric patients has not been established in clinical trials though antidepressants are associated with an increased risk of suicidal thought and behaviour in patients under 24 years. Clinical studies in geriatric patients showed to significant difference in response to vilazodone compared to younger patients. Geriatric patients should be started at a lower dose and titrated to an effective dose as they are more likely to have other comorbidities. Dosage adjustments are not necessary for patients of different genders or with reduced hepatic and renal function. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Viibryd •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vilazodone is an antidepressant agent used for the treatment of major depressive disorder that targets the 5-HT transporter and 5-HT1A receptors.

The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Vilazodone interact? Information: •Drug A: Bupropion •Drug B: Vilazodone •Severity: MAJOR •Description: The metabolism of Vilazodone can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vilazodone is approved for treatment of major depressive disorder. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vilazodone increases serotonin levels in the brain by inhibiting the reuptake of serotonin while acting as a partial agonist on serotonin-1A receptors. Due to this activity vilazodone has sometimes been referred to as a selective partial agonist and reuptake inhibitor (SPARI). •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vilazodone selectively inhibits serotonin reuptake in the central nervous system as well as acting as a partial agonist of 5HT-1A receptors. The exact mechanism for how these effects translate to its antidepressant effects are not known, though there is an association between these effects and antidepressive activity. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Vilazodone's bioavailability is 72% when taken with food. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vilazodone's volume of distribution is unknown but large •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 96-99%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vilazodone is mainly metabolized by cytochrome P450(CYP)3A4 and also to a minor extent by CYP2C19 and CYP 2D6. Although the metabolic pathway for vilazodone has not been fully studied, a proposed mechanism for metabolism in rats was published in 2017. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): 1% of the dose is recovered unchanged in the urine and 2% of the dose is recovered unchanged in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): 25 hours. Other studies show a half life of 24±5.2h with a single 40mg dose and 28.9±3.2h with repeated doses. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance of vilazodone is 19.9-25.1L/h in patients with mild to moderate renal impairment compared to 26.4-26.9L/h in healthy controls. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): There is a lack of clinical studies of vilazodone in pregnancy. Animal studies have shown the effects on offspring to be reduced fetal weight, increased mortality, delayed maturation, and decreased fertility in adulthood at doses well above the maximum recommended human dose. Clinical cases of fetal and neonatal exposure to SSRIs and SNRIs have lead to a number of complications including respiratory distress, seizures, and temperature instability. It is not know whether vilazodone is excreted in the breast milk of nursing mothers but animal studies show this is the case for rats. The risk and benefit of breast feeding while taking vilazodone for mother and child must be considered before a decision is made. Safety and effectiveness in pediatric patients has not been established in clinical trials though antidepressants are associated with an increased risk of suicidal thought and behaviour in patients under 24 years. Clinical studies in geriatric patients showed to significant difference in response to vilazodone compared to younger patients. Geriatric patients should be started at a lower dose and titrated to an effective dose as they are more likely to have other comorbidities. Dosage adjustments are not necessary for patients of different genders or with reduced hepatic and renal function. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Viibryd •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vilazodone is an antidepressant agent used for the treatment of major depressive disorder that targets the 5-HT transporter and 5-HT1A receptors. Output: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Viloxazine interact?

•Drug A: Bupropion •Drug B: Viloxazine •Severity: MINOR •Description: The serum concentration of Bupropion can be increased when it is combined with Viloxazine. •Extended Description: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Viloxazine is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Viloxazine is a serotonin-norepinephrine modulating agent that has been used as a treatment for depression and Attention Deficit Hyperactivity Disorder (ADHD). Although it is not a stimulant agent, viloxazine produces amphetamine-like CNS stimulant effects without a risk for drug abuse or dependence. Viloxazine does not produce sedative anticholinergic or adrenergic effects. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder in children characterized by inattention and hyperactivity. In current literature, the pathophysiology of ADHD is understood to involve the imbalance of neurotransmitters, especially dopamine (DA) and norepinephrine (NE). The mechanism of action of viloxazine has not been fully elucidated; however, viloxazine is believed to work by modulating the monoaminergic neurotransmitter systems. Viloxazine is a selective and moderate norepinephrine reuptake inhibitor that binds to the norepinephrine transporter and inhibits the reuptake of norepinephrine. It thereby increases extracellular norepinephrine levels across several brain regions. Viloxazine potentiates serotonergic effects: it was shown to enhance neuronal sensitivity to serotonin and increase serotonin levels in the brain. In vitro, viloxazine is an antagonist at 5-HT 2B receptors and an agonist 5-HT 2C receptors. 5-HT 2B receptors expressed on GABAergic interneurons are involved in tonic inhibitory control of serotonin neurons that innervate the medial prefrontal context; thus, antagonism of 5-HT 2B receptors may result in disinhibition and enhanced serotonin release in the brain region. There is conflicting evidence in the literature that viloxazine increases dopamine levels in the brain via direct or indirect effects. For example, the norepinephrine transporter is also involved in the reuptake of dopamine in the prefrontal cortex and stimulation of 5-HT 2C receptors facilitates DA release and enhances dopaminergic transmission in the brain. As dopamine dysregulation in the prefrontal cortex and amygdala is implicated in ADHD pathophysiology, the impact of viloxazine on dopamine levels may contribute to its mechanism of action. However, there is insufficient evidence to conclude this. Viloxazine has a negligible impact on dopamine in the nucleus accumbens and is not associated with an abuse risk. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Viloxazine is rapidly absorbed following oral administration. The relative bioavailability of viloxazine extended-release relative to an immediate-release formulation was about 88%. Viloxazine C max and AUC increase proportionally over a dosage range from 100 mg to 600 mg once daily. The C max ranges between 540 and 1600 ng/mL. Following administration of a single 200 mg dose, the median T max was approximately five hours, with a range of three to nine hours. Steady-state was reached after two days of once-daily administration, and no accumulation was observed. A high-fat meal decreases C max and AUC by about 9% and 8%, respectively, and delays T max by two hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution was 0.73 ± 0.28 L/kg following intravenous administration. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Viloxazine is 76-82% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 10 mcg/mL. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Viloxazine undergoes CYP2D6-mediated 5-hydroxylation to form 5-hydroxyviloxazine. This metabolite can be glucuronidated by UGT1A9 and UGT2B15 to form 5-hydroxyviloxazine glucuronide, which is the major metabolite detected in plasma. Viloxazine can also be glucuronidated to form Viloxazine N-carbamoyl glucuronide. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Viloxazine is primarily excreted via renal elimination. After administration of radiolabeled viloxazine, 90% of the dose was recovered in urine within the first 24 hours post-dose. Less than 1% of the dose is excreted in the feces. About 12-15% of the total drug is eliminated as unchanged parent drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): The mean (± SD) half-life of viloxazine was 7.02 (± 4.74) hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance rate was 124 ± 11 mL/hour/kg following intravenous administration. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 of viloxazine was 2000 mg/kg in rats. There is limited clinical experience with viloxazine overdose. According to case reports in the literature and postmarketing reports, doses ranging from 1000 mg to 6500 mg, which are 1.7 to 10.8 times the maximum recommended daily dose, resulted in overdose with drowsiness as the most reported symptom. Impaired consciousness, diminished reflexes, and increased heart rate have also been reported. There is no specific antidote for viloxazine overdose. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Qelbree •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Viloxazina Viloxazine Viloxazinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Viloxazine is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults in children.

Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. The severity of the interaction is minor.

Question: Does Bupropion and Viloxazine interact? Information: •Drug A: Bupropion •Drug B: Viloxazine •Severity: MINOR •Description: The serum concentration of Bupropion can be increased when it is combined with Viloxazine. •Extended Description: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Viloxazine is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Viloxazine is a serotonin-norepinephrine modulating agent that has been used as a treatment for depression and Attention Deficit Hyperactivity Disorder (ADHD). Although it is not a stimulant agent, viloxazine produces amphetamine-like CNS stimulant effects without a risk for drug abuse or dependence. Viloxazine does not produce sedative anticholinergic or adrenergic effects. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder in children characterized by inattention and hyperactivity. In current literature, the pathophysiology of ADHD is understood to involve the imbalance of neurotransmitters, especially dopamine (DA) and norepinephrine (NE). The mechanism of action of viloxazine has not been fully elucidated; however, viloxazine is believed to work by modulating the monoaminergic neurotransmitter systems. Viloxazine is a selective and moderate norepinephrine reuptake inhibitor that binds to the norepinephrine transporter and inhibits the reuptake of norepinephrine. It thereby increases extracellular norepinephrine levels across several brain regions. Viloxazine potentiates serotonergic effects: it was shown to enhance neuronal sensitivity to serotonin and increase serotonin levels in the brain. In vitro, viloxazine is an antagonist at 5-HT 2B receptors and an agonist 5-HT 2C receptors. 5-HT 2B receptors expressed on GABAergic interneurons are involved in tonic inhibitory control of serotonin neurons that innervate the medial prefrontal context; thus, antagonism of 5-HT 2B receptors may result in disinhibition and enhanced serotonin release in the brain region. There is conflicting evidence in the literature that viloxazine increases dopamine levels in the brain via direct or indirect effects. For example, the norepinephrine transporter is also involved in the reuptake of dopamine in the prefrontal cortex and stimulation of 5-HT 2C receptors facilitates DA release and enhances dopaminergic transmission in the brain. As dopamine dysregulation in the prefrontal cortex and amygdala is implicated in ADHD pathophysiology, the impact of viloxazine on dopamine levels may contribute to its mechanism of action. However, there is insufficient evidence to conclude this. Viloxazine has a negligible impact on dopamine in the nucleus accumbens and is not associated with an abuse risk. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Viloxazine is rapidly absorbed following oral administration. The relative bioavailability of viloxazine extended-release relative to an immediate-release formulation was about 88%. Viloxazine C max and AUC increase proportionally over a dosage range from 100 mg to 600 mg once daily. The C max ranges between 540 and 1600 ng/mL. Following administration of a single 200 mg dose, the median T max was approximately five hours, with a range of three to nine hours. Steady-state was reached after two days of once-daily administration, and no accumulation was observed. A high-fat meal decreases C max and AUC by about 9% and 8%, respectively, and delays T max by two hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution was 0.73 ± 0.28 L/kg following intravenous administration. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Viloxazine is 76-82% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 10 mcg/mL. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Viloxazine undergoes CYP2D6-mediated 5-hydroxylation to form 5-hydroxyviloxazine. This metabolite can be glucuronidated by UGT1A9 and UGT2B15 to form 5-hydroxyviloxazine glucuronide, which is the major metabolite detected in plasma. Viloxazine can also be glucuronidated to form Viloxazine N-carbamoyl glucuronide. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Viloxazine is primarily excreted via renal elimination. After administration of radiolabeled viloxazine, 90% of the dose was recovered in urine within the first 24 hours post-dose. Less than 1% of the dose is excreted in the feces. About 12-15% of the total drug is eliminated as unchanged parent drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): The mean (± SD) half-life of viloxazine was 7.02 (± 4.74) hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance rate was 124 ± 11 mL/hour/kg following intravenous administration. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The oral LD 50 of viloxazine was 2000 mg/kg in rats. There is limited clinical experience with viloxazine overdose. According to case reports in the literature and postmarketing reports, doses ranging from 1000 mg to 6500 mg, which are 1.7 to 10.8 times the maximum recommended daily dose, resulted in overdose with drowsiness as the most reported symptom. Impaired consciousness, diminished reflexes, and increased heart rate have also been reported. There is no specific antidote for viloxazine overdose. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Qelbree •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Viloxazina Viloxazine Viloxazinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Viloxazine is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults in children. Output: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. The severity of the interaction is minor.

Does Bupropion and Voriconazole interact?

•Drug A: Bupropion •Drug B: Voriconazole •Severity: MINOR •Description: The serum concentration of Bupropion can be increased when it is combined with Voriconazole. •Extended Description: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of esophageal candidiasis, cadidemia, invasive pulmonary aspergillosis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Voriconazole is a fungistatic triazole antifungal used to treat infections by inhibiting fungal growth. It is known to cause hepatotoxic and photosensitivity reactions in some patients. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Voriconazole is used to treat fungal infections caused by a variety of organisms but including Aspergillus spp. and Candida spp. Voriconazole is a triazole antifungal exhibiting fungistatic activity against fungal pathogens. Like other triazoles, voriconazole binds to 14-alpha sterol demethylase, also known as CYP51, and inhibits the demethylation of lanosterol as part of the ergosterol synthesis pathway in yeast and other fungi. The lack of sufficient ergosterol disrupts fungal cell membrane function and limits fungal cell growth. With fungal growth limited, the host's immune system is able to clear the invading organism. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The oral bioavailability is estimated to be 96% in healthy adults. Population pharmacokinetic studies report a reduced bioavailability pediatric patients with a mean of 61.8% (range 44.6–64.5%) thought to be due to differences in first-pass metabolism or due to differences in diet. Of note, transplant patients also have reduced bioavailability but this is known to increase with time after transplantation and may be due in part to gastrointestinal upset from surgery and some transplant medications. Tmax is 1-2 hours with oral administration. When administered with a high-fat meal Cmax decreases by 34% and AUC by 24%. pH does not have an effect on absorption of voriconazole. Differences in Cmax and AUC have been observed between healthy adult males and females with Cmax increasing by 83% and AUC by 113% although this has not been observed to significantly impact medication safety profiles. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The estimated volume of distribution of voriconazole is 4.6 L/kg. Population pharmacokinetic studies estimate the median volume of distribution to be 77.6 L with the central compartment estimated at 1.07 L/kg Voriconazole is known to achieve therapeutic concentrations in many tissues including the brain, lungs, liver, spleen, kidneys, and heart. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Voriconazole is 58% bound to plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Voriconazole undergoes extensive hepatic metabolism through cytochrome enzymes CYP2C9, CYP2C19, and CYP3A4. CYP2C19 mediates N-oxidation with an apparent Km of 14 μM and an apparent Vmax of 0.22 nmol/min/nmol CYP2C19. Voriconazole N-oxide is the major circulating metabolite, accounting for 72% of radiolabeled metabolites found. CYP3A4 contributes to N-oxidation with a Km of 16 μM and Vmax of 0.05 nmol/min/nmol CYP3A4 as well as 4-hydroxylation with a Km of 11 μM and a Vmax of 0.10 nmol/min/nmol CYP3A4. CYP3A5 and CYP3A7 provide minor contributions to N-oxidation and 4-hydroxylation. The N-oxide and 4-hydroxylated metabolites undergo glucuronidation and are excreted through the urine with other minor glucuronidated metabolites. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Voriconazole follows non-linear kinetics and has a terminal half-life of elimination which is dose-dependent. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of voriconazole is estimated to be a mean of 5.25-7 L/h in healthy adults for the linear portion of the drug's kinetics. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include photophobia and possible QTc prolongation. In case of overdose, supportive care and ECG monitoring are recommended. Activated charcoal may aid in the removal of unabsorbed drug. Voriconazole is cleared by hemodialysis at a rate of 121 mL/min which may be helpful in removing absorbed drug. Carcinogenicity studies found hepatocellular adenomas in female rats at doses of 50 mg/kg and hepatocellular carcinomas found in male rats at doses of 6 and 50 mg/kg. These doses are equivalent to 0.2 and 1.6 times the recommended maintenance dose (RMD). Studies in mice detected hepatocellular carcinomas in males at doses of 100 mg/kg or 1.4 times the RMD. Hepatocellular adenomas were detected in both male and female mice. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Vfend •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Voriconazol Voriconazole Voriconazolum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Voriconazole is a triazole compound used to treat fungal infections.

Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. The severity of the interaction is minor.

Question: Does Bupropion and Voriconazole interact? Information: •Drug A: Bupropion •Drug B: Voriconazole •Severity: MINOR •Description: The serum concentration of Bupropion can be increased when it is combined with Voriconazole. •Extended Description: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of esophageal candidiasis, cadidemia, invasive pulmonary aspergillosis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Voriconazole is a fungistatic triazole antifungal used to treat infections by inhibiting fungal growth. It is known to cause hepatotoxic and photosensitivity reactions in some patients. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Voriconazole is used to treat fungal infections caused by a variety of organisms but including Aspergillus spp. and Candida spp. Voriconazole is a triazole antifungal exhibiting fungistatic activity against fungal pathogens. Like other triazoles, voriconazole binds to 14-alpha sterol demethylase, also known as CYP51, and inhibits the demethylation of lanosterol as part of the ergosterol synthesis pathway in yeast and other fungi. The lack of sufficient ergosterol disrupts fungal cell membrane function and limits fungal cell growth. With fungal growth limited, the host's immune system is able to clear the invading organism. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The oral bioavailability is estimated to be 96% in healthy adults. Population pharmacokinetic studies report a reduced bioavailability pediatric patients with a mean of 61.8% (range 44.6–64.5%) thought to be due to differences in first-pass metabolism or due to differences in diet. Of note, transplant patients also have reduced bioavailability but this is known to increase with time after transplantation and may be due in part to gastrointestinal upset from surgery and some transplant medications. Tmax is 1-2 hours with oral administration. When administered with a high-fat meal Cmax decreases by 34% and AUC by 24%. pH does not have an effect on absorption of voriconazole. Differences in Cmax and AUC have been observed between healthy adult males and females with Cmax increasing by 83% and AUC by 113% although this has not been observed to significantly impact medication safety profiles. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The estimated volume of distribution of voriconazole is 4.6 L/kg. Population pharmacokinetic studies estimate the median volume of distribution to be 77.6 L with the central compartment estimated at 1.07 L/kg Voriconazole is known to achieve therapeutic concentrations in many tissues including the brain, lungs, liver, spleen, kidneys, and heart. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Voriconazole is 58% bound to plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Voriconazole undergoes extensive hepatic metabolism through cytochrome enzymes CYP2C9, CYP2C19, and CYP3A4. CYP2C19 mediates N-oxidation with an apparent Km of 14 μM and an apparent Vmax of 0.22 nmol/min/nmol CYP2C19. Voriconazole N-oxide is the major circulating metabolite, accounting for 72% of radiolabeled metabolites found. CYP3A4 contributes to N-oxidation with a Km of 16 μM and Vmax of 0.05 nmol/min/nmol CYP3A4 as well as 4-hydroxylation with a Km of 11 μM and a Vmax of 0.10 nmol/min/nmol CYP3A4. CYP3A5 and CYP3A7 provide minor contributions to N-oxidation and 4-hydroxylation. The N-oxide and 4-hydroxylated metabolites undergo glucuronidation and are excreted through the urine with other minor glucuronidated metabolites. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): Voriconazole follows non-linear kinetics and has a terminal half-life of elimination which is dose-dependent. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of voriconazole is estimated to be a mean of 5.25-7 L/h in healthy adults for the linear portion of the drug's kinetics. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include photophobia and possible QTc prolongation. In case of overdose, supportive care and ECG monitoring are recommended. Activated charcoal may aid in the removal of unabsorbed drug. Voriconazole is cleared by hemodialysis at a rate of 121 mL/min which may be helpful in removing absorbed drug. Carcinogenicity studies found hepatocellular adenomas in female rats at doses of 50 mg/kg and hepatocellular carcinomas found in male rats at doses of 6 and 50 mg/kg. These doses are equivalent to 0.2 and 1.6 times the recommended maintenance dose (RMD). Studies in mice detected hepatocellular carcinomas in males at doses of 100 mg/kg or 1.4 times the RMD. Hepatocellular adenomas were detected in both male and female mice. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Vfend •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Voriconazol Voriconazole Voriconazolum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Voriconazole is a triazole compound used to treat fungal infections. Output: Bupropion is extensively metabolized to hydroxybupropion by CYP2B6. The severity of the interaction is minor.

Does Bupropion and Vortioxetine interact?

•Drug A: Bupropion •Drug B: Vortioxetine •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Bupropion is combined with Vortioxetine. •Extended Description: Co-administration with strong CYP2D6 inhibitors, such as bupropion, may result in an increase in the concentration of vortioxetine.4 Bupropion has been associated with several cases of serotonin syndrome. There may be a potential risk for additive serotonergic effects during concomitant administration of bupropion and vortioxetine, which leads to fluctuations in heart rate, blood pressure, dilated pupils, agitation, confusion, sweating, diarrhea, and sometimes death. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vortioxetine is indicated for the treatment of major depressive disorder (MDD). •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vortioxetine binds with high affinity to the human serotonin transporter (Ki=1.6 nM), but not to the norepinephrine (Ki=113 nM) or dopamine (Ki>1000 nM) transporters. Vortioxetine potently and selectively inhibits reuptake of serotonin by inhibition of the serotonin transporter (IC50=5.4 nM). Specifically, vortioxetine binds to 5­HT3 (Ki=3.7 nM), 5­HT1A (Ki=15 nM), 5­HT7 (Ki=19 nM), 5­HT1D (Ki=54 nM), and 5­HT1B (Ki=33 nM), receptors and is a 5­HT3, 5­HT1D, and 5­HT7 receptor antagonist, 5­HT1B receptor partial agonist, and 5­HT1A receptor agonist. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vortioxetine is classified as a serotonin modulator and simulator (SMS) as it has a multimodal mechanism of action towards the serotonin neurotransmitter system whereby it simultaneously modulates one or more serotonin receptors and inhibits the reuptake of serotonin. More specifically, vortioxetine acts via the following biological mechanisms: as a serotonin reuptake inhibitor (SRI) through inhibition of the serotonin transporter, while also acting as a partial agonist of the 5-HT1B receptor, an agonist of 5-HT1A, and antagonist of the 5-HT3, 5-HT1D, and 5-HT7 receptors. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution of vortioxetine is approximately 2600 L, indicating extensive extravascular distribution. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The plasma protein binding of vortioxetine in humans is 98%, independent of plasma concentrations. No apparent difference in the plasma protein binding between healthy subjects and subjects with hepatic (mild, moderate) or renal (mild, moderate, severe, ESRD) impairment is observed. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following a single oral dose of [14C]­labeled vortioxetine, approximately 59% and 26% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours. •Half-life (Drug A): 24 hours •Half-life (Drug B): Mean terminal half­life is approximately 66 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The most commonly reported adverse effects during clinical trials were nausea, diarrhea, and dry mouth. The FDA label includes a blackbox warning for the following risks and complications: serotonin syndrome, especially when combined with other serotonergic agents; increased risk of abnormal bleeding, especially when combined with NSAIDs, aspirin, or other drugs that affect coagulation; activation of mania/hypomania; hyponatremia; and suicidal thoughts and behaviour in children, adolescents, and young adults. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Brintellix, Trintellix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vortioxetine is a serotonin modulating antidepressant indicated for the treatment of major depressive disorder (MDD).

Co-administration with strong CYP2D6 inhibitors, such as bupropion, may result in an increase in the concentration of vortioxetine.4 Bupropion has been associated with several cases of serotonin syndrome. There may be a potential risk for additive serotonergic effects during concomitant administration of bupropion and vortioxetine, which leads to fluctuations in heart rate, blood pressure, dilated pupils, agitation, confusion, sweating, diarrhea, and sometimes death. The severity of the interaction is moderate.

Question: Does Bupropion and Vortioxetine interact? Information: •Drug A: Bupropion •Drug B: Vortioxetine •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Bupropion is combined with Vortioxetine. •Extended Description: Co-administration with strong CYP2D6 inhibitors, such as bupropion, may result in an increase in the concentration of vortioxetine.4 Bupropion has been associated with several cases of serotonin syndrome. There may be a potential risk for additive serotonergic effects during concomitant administration of bupropion and vortioxetine, which leads to fluctuations in heart rate, blood pressure, dilated pupils, agitation, confusion, sweating, diarrhea, and sometimes death. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Vortioxetine is indicated for the treatment of major depressive disorder (MDD). •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Vortioxetine binds with high affinity to the human serotonin transporter (Ki=1.6 nM), but not to the norepinephrine (Ki=113 nM) or dopamine (Ki>1000 nM) transporters. Vortioxetine potently and selectively inhibits reuptake of serotonin by inhibition of the serotonin transporter (IC50=5.4 nM). Specifically, vortioxetine binds to 5­HT3 (Ki=3.7 nM), 5­HT1A (Ki=15 nM), 5­HT7 (Ki=19 nM), 5­HT1D (Ki=54 nM), and 5­HT1B (Ki=33 nM), receptors and is a 5­HT3, 5­HT1D, and 5­HT7 receptor antagonist, 5­HT1B receptor partial agonist, and 5­HT1A receptor agonist. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Vortioxetine is classified as a serotonin modulator and simulator (SMS) as it has a multimodal mechanism of action towards the serotonin neurotransmitter system whereby it simultaneously modulates one or more serotonin receptors and inhibits the reuptake of serotonin. More specifically, vortioxetine acts via the following biological mechanisms: as a serotonin reuptake inhibitor (SRI) through inhibition of the serotonin transporter, while also acting as a partial agonist of the 5-HT1B receptor, an agonist of 5-HT1A, and antagonist of the 5-HT3, 5-HT1D, and 5-HT7 receptors. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution of vortioxetine is approximately 2600 L, indicating extensive extravascular distribution. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The plasma protein binding of vortioxetine in humans is 98%, independent of plasma concentrations. No apparent difference in the plasma protein binding between healthy subjects and subjects with hepatic (mild, moderate) or renal (mild, moderate, severe, ESRD) impairment is observed. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following a single oral dose of [14C]­labeled vortioxetine, approximately 59% and 26% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours. •Half-life (Drug A): 24 hours •Half-life (Drug B): Mean terminal half­life is approximately 66 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The most commonly reported adverse effects during clinical trials were nausea, diarrhea, and dry mouth. The FDA label includes a blackbox warning for the following risks and complications: serotonin syndrome, especially when combined with other serotonergic agents; increased risk of abnormal bleeding, especially when combined with NSAIDs, aspirin, or other drugs that affect coagulation; activation of mania/hypomania; hyponatremia; and suicidal thoughts and behaviour in children, adolescents, and young adults. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Brintellix, Trintellix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Vortioxetine is a serotonin modulating antidepressant indicated for the treatment of major depressive disorder (MDD). Output: Co-administration with strong CYP2D6 inhibitors, such as bupropion, may result in an increase in the concentration of vortioxetine.4 Bupropion has been associated with several cases of serotonin syndrome. There may be a potential risk for additive serotonergic effects during concomitant administration of bupropion and vortioxetine, which leads to fluctuations in heart rate, blood pressure, dilated pupils, agitation, confusion, sweating, diarrhea, and sometimes death. The severity of the interaction is moderate.

Does Bupropion and Voxelotor interact?

•Drug A: Bupropion •Drug B: Voxelotor •Severity: MODERATE •Description: The metabolism of Voxelotor can be decreased when combined with Bupropion. •Extended Description: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): In the US, voxelotor is indicated to treat sickle cell disease in both adult and pediatric patients aged 4 years and older. In Europe, it is indicated for the treatment of hemolytic anemia due to sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older as monotherapy or in combination with hydroxyurea. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Voxelotor increases hemoglobin (Hb) oxygen affinity in a dose-dependent manner. It has led to up to a 40% increase in hemoglobin in clinical trials. Voxelotor may inhibit red blood cell sickling, attenuate red blood cell deformability, and reduce whole blood viscosity. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Sickle cell disease is characterized by deoxygenated sickle hemoglobin (HbS) polymerization. The genetic mutation causing this disease leads to the formation of abnormal, sickle-shaped red blood cells that aggregate and block blood vessels throughout the body, causing vaso-occlusive crises. Sickle-shaped red blood cells cannot effectively bind oxygen, thus incapable of allowing normal blood flow to organs. Voxelotor increases Hb oxygen affinity. It binds reversibly to hemoglobin (Hb) by forming a covalent bond with the N‐terminal valine of the α‐chain of the protein, resulting in an allosteric modification of Hb. Voxelotor stabilizes the oxygenated Hb state and prevents HbS polymerization by increasing hemoglobin’s affinity for oxygen. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Voxelotor is rapidly absorbed after oral administration, with a plasma T max of 2 hours. T max in the red blood cells ranges from 17-24 hours. The C max in whole blood and red blood cells occur 6 and 18 hours after an oral dose, respectively. Consumption of a high-fat meal with voxelotor significantly increased exposure to the drug during clinical trials. After a daily dose of either 300, 600, or 900 mg for a period of 15 days, when steady-state concentrations were reached, the average RBC Cmax for the respective doses were measured to be 4950, 9610 and 14 000 μg*h mL−1, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution of voxelotor in the central compartment is 338L and 72.2L in the plasma. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The protein binding of voxeletor is 99.8% in vitro. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Voxeletor is heavily metabolized via two phases. Phase I metabolism consists of oxidation and reduction, while phase II metabolism consists of glucuronidation. Voseletor is oxidized mainly by CYP3A4 and by CYP2C19, CYP2B6, and CYP2C9, to a lesser extent. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 62.6% of the oral dose is found in the feces, of which 33.3% is an unchanged drug. About 35.5% of the dose is recovered in urine, with only 0.08% as the unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): The plasma elimination half-life of voxelotor in sickle cell disease patients is about 35.5 hours. The mean half-life in the red blood cell is 60 days. In one study, the average plasma half-life of voxelotor was 50 hours in patients with sickle cell disease, compared with 61–85 hours in healthy subjects. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent oral clearance of voxelotor is approximately 6.7 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The LD 50 information and overdose information is unavailable at this time. Current clinical study results suggest that dose-limiting toxicities of voxelotor are unlikely. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Oxbryta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Voxelotor is a drug used to inhibit the polymerization of hemoglobin S, preventing the painful and sometimes lethal vaso-occlusive crises associated with sickle cell disease.

When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. The severity of the interaction is moderate.

Question: Does Bupropion and Voxelotor interact? Information: •Drug A: Bupropion •Drug B: Voxelotor •Severity: MODERATE •Description: The metabolism of Voxelotor can be decreased when combined with Bupropion. •Extended Description: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): In the US, voxelotor is indicated to treat sickle cell disease in both adult and pediatric patients aged 4 years and older. In Europe, it is indicated for the treatment of hemolytic anemia due to sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older as monotherapy or in combination with hydroxyurea. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Voxelotor increases hemoglobin (Hb) oxygen affinity in a dose-dependent manner. It has led to up to a 40% increase in hemoglobin in clinical trials. Voxelotor may inhibit red blood cell sickling, attenuate red blood cell deformability, and reduce whole blood viscosity. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Sickle cell disease is characterized by deoxygenated sickle hemoglobin (HbS) polymerization. The genetic mutation causing this disease leads to the formation of abnormal, sickle-shaped red blood cells that aggregate and block blood vessels throughout the body, causing vaso-occlusive crises. Sickle-shaped red blood cells cannot effectively bind oxygen, thus incapable of allowing normal blood flow to organs. Voxelotor increases Hb oxygen affinity. It binds reversibly to hemoglobin (Hb) by forming a covalent bond with the N‐terminal valine of the α‐chain of the protein, resulting in an allosteric modification of Hb. Voxelotor stabilizes the oxygenated Hb state and prevents HbS polymerization by increasing hemoglobin’s affinity for oxygen. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Voxelotor is rapidly absorbed after oral administration, with a plasma T max of 2 hours. T max in the red blood cells ranges from 17-24 hours. The C max in whole blood and red blood cells occur 6 and 18 hours after an oral dose, respectively. Consumption of a high-fat meal with voxelotor significantly increased exposure to the drug during clinical trials. After a daily dose of either 300, 600, or 900 mg for a period of 15 days, when steady-state concentrations were reached, the average RBC Cmax for the respective doses were measured to be 4950, 9610 and 14 000 μg*h mL−1, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution of voxelotor in the central compartment is 338L and 72.2L in the plasma. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The protein binding of voxeletor is 99.8% in vitro. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Voxeletor is heavily metabolized via two phases. Phase I metabolism consists of oxidation and reduction, while phase II metabolism consists of glucuronidation. Voseletor is oxidized mainly by CYP3A4 and by CYP2C19, CYP2B6, and CYP2C9, to a lesser extent. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): About 62.6% of the oral dose is found in the feces, of which 33.3% is an unchanged drug. About 35.5% of the dose is recovered in urine, with only 0.08% as the unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): The plasma elimination half-life of voxelotor in sickle cell disease patients is about 35.5 hours. The mean half-life in the red blood cell is 60 days. In one study, the average plasma half-life of voxelotor was 50 hours in patients with sickle cell disease, compared with 61–85 hours in healthy subjects. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent oral clearance of voxelotor is approximately 6.7 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The LD 50 information and overdose information is unavailable at this time. Current clinical study results suggest that dose-limiting toxicities of voxelotor are unlikely. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Oxbryta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Voxelotor is a drug used to inhibit the polymerization of hemoglobin S, preventing the painful and sometimes lethal vaso-occlusive crises associated with sickle cell disease. Output: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate and/or an increased risk, incidence, or severity of adverse effects associated with exposure to this substrate. The severity of the interaction is moderate.

Does Bupropion and Warfarin interact?

•Drug A: Bupropion •Drug B: Warfarin •Severity: MODERATE •Description: Bupropion may decrease the excretion rate of Warfarin which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated for: 1) Prophylaxis and treatment of venous thromboembolism and related pulmonary embolism. 2) Prophylaxis and treatment of thromboembolism associated with atrial fibrillation. 3) Prophylaxis and treatment of thromboembolism associated with cardiac valve replacement. 4) Use as adjunct therapy to reduce mortality, recurrent myocardial infarction, and thromboembolic events post myocardial infarction. Off-label uses include: 1) Secondary prevention of stroke and transient ischemic attacks in patients with rheumatic mitral valve disease but without atrial fibrillation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Warfarin is an anticoagulant, as such it disrupts the coagulation cascade to reduce frequency and extent of thrombus formation. In patients with deep vein thrombosis or atrial fibrillation there is an increased risk of thrombus formation due to the reduced movement of blood. For patients with cardiac valve disease or valve replacements this increased coagulability is due to tissue damage. Thrombi due to venous thrombosis can travel to the lungs and become pulmonary emboli, blocking circulation to a portion of lung tissue. Thrombi which form in the heart can travel to the brain and cause ischemic strokes. Prevention of these events is the primary goal of warfarin therapy. Limitation of thrombus formation is also a source of adverse effects. In patients with atheroscelotic plaques rupture typically results in thrombus formation. When these patients are anticoagulated plaque rupture can allow the escape of cholesterol from the lipid core in the form of atheroemboli or cholesterol microemboli. These emboli are smaller than thrombi and block smaller vessels, usually less than 200 μm in diameter. The consequences of this are varied and depend on the location of the blockage. Effects include visual disturbances, acute kidney injury or worsening of chronic kidney disease, central nervous system ischemia, and purple or blue toe syndrome. Blue toe syndrome can be reversed if it has not progressed to tissue necrosis but the other effects of microemboli are often permanent. Antocoagulation appears to mediate warfarin-related nephropathy, a seemingly spontaneous kidney injury or worsening of chronic kidney disease associated with warfarin therapy. Nephropathy in this case appears to be due to increased passage of red blood cells through the glomerulus and subsequent blockage of renal tubules with red blood cell casts. This is worsened or possibly triggered by pre-existing kidney damage. Increased risk of warfarin-related nephropathy occurs at INRs over 3.0 but risk does not increase as a function of INR beyond this point. Warfarin has been linked to the development of calciphylaxis. This is thought to be due to warfarin's inhibition of vitamin K recycling as VKA is needed for the carboxylation of matrix Gla protein. This protein is an anti-calcification factor and its inhibition through preventing the carboxylation step in its production leads to a shift in calcification balance in favor of calciphylaxis. Tissue necrosis can occur early on in warfarin therapy. This is attributable to half lives of the clotting factors impacted by inhibition of vitamin K recycling. Proteins C and S are anticoagulation factors with half lives of 8 and 24 hours respectively. The coagulation factors IX, X, VII, and thrombin (factor II) have half lives of 24, 36, 6, and 50 hours respectively. This means proteins C and S are inactivated sooner than pro-coagulation proteins, with the exception of factor VII, resulting in a pro-thrombotic state for the first few days of therapy. Thrombi which form in this time period can occlude arterioles in various locations, blocking blood flow and causing tissue necrosis due to ischemia. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Warfarin is a [vitamin K] antagonist which acts to inhibit the production of vitamin K by vitamin K epoxide reductase. The reduced form of vitamin K, vitamin KH 2 is a cofactor used in the γ-carboxylation of coagulation factors VII, IX, X, and thrombin. Carboxylation induces a conformational change allowing the factors to bind Ca and to phospholipid surfaces. Uncarboxylated factors VII, IX, X, and thrombin are biologically inactive and therefore serve to interrupt the coagulation cascade. The endogenous anticoagulation proteins C and S also require γ-carboxylation to function. This is particularly true in the case of thrombin which must be activated in order to form a thrombus. vitamin KH 2 is converted to vitamin K epoxide as part of the γ-carboxylation reaction catalyzed by γ-glutamyl carboxylase. Vitamin K epoxide is then converted to vitamin K 1 by vitamin K epoxide reductase then back to vitamin KH 2 by vitamin K reductase. Warfarin binds to vitamin K epoxide reductase complex subunit 1 and irreversibly inhibits the enzyme thereby stopping the recycling of vitamin K by preventing the conversion of vitamin K epoxide to vitamin K 1. This process creates a hypercoagulable state for a short time as proteins C and S degrade first with half lives of 8 and 24 hours, with the exception of factor VII which has a half life of 6 hours. Factors IX, X, and finally thrombin degrade later with half lives of 24, 36, and 50 hours resulting in a dominant anticoagulation effect. In order to reverse this anticoagulation vitamin K must be supplied, either exogenously or by removal of the vitamin K epoxide reductase inhibition, and time allowed for new coagulation factors to be synthesized. It takes approximately 2 days for new coagulation factors to be synthesized in the liver. Vitamin K 2, functionally identical to vitamin K 1, is synthesized by gut bacteria leading to interactions with antibiotics as elimination of these bacteria can reduce vitamin K 2 16 •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Completely absorbed from the GI tract. The mean Tmax for warfarin sodium tablets is 4 hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vd of 0.14 L/kg. Warfarin has a distrubution phase lasting 6-12 hours. It is known to cross the placenta and achieves fetal serum concentrations similar to maternal concentrations. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 99% bound primarily to albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Metabolism of warfarin is both stereo- and regio-selective. The major metabolic pathway is oxidation to various hydroxywarfarins, comprising 80-85% of the total metabolites. CYP2C9 is the major enzyme catalyzing the 6- and 7-hydroxylation of S-warfarin while 4'-hydroxylation occurs through CYP2C18 with minor contributions from CYP2C19. R-warfarin is metabolized to 4'-hydroxywarfarin by CYP2C8 with some contirbuting by CYP2C19, 6- and 8-hydroxywarfarin by CYP1A2 and CYP2C19, 7-hydroxywarfarin by CYP1A2 and CYP2C8, and lastly to 10-hydroxywarfarin by CYP3A4. The 10-hydroxywarfarin metabolite as well as a benzylic alcohol metabolite undergo an elimination step to form dehydrowarfarin. The minor pathway of metabolism is the reduction of the ketone group to warfarin alcohols, comprising 20% of the metabolites. Limited conjugation occurs with sulfate and gluronic acid groups but these metabolites have only been confirmed for R-hydroxywarfarins. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): The elimination of warfarin is almost entirely by metabolism with a small amount excreted unchanged. 80% of the total dose is excreted in the urine with the remaining 20% appearing in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): R-warfarin is cleared more slowly than S-warfarin, at about half the rate. T 1/2 for R-warfarin is 37-89 hours. T 1/2 for S-warfarin is 21-43 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance of warfarin varies depending on CYP2C9 genotype. The *2 and *3 alleles appear in the Caucasian population at frequencies of 11% and 7% and are known to reduce clearance warfarin. Additional clearance reducing genotypes include the *5, *6, *9 and *11 alleles. Genotypes for which population clearance estimates have been found are listed below. *1/*1 = 0.065 mL/min/kg *1/*2, *1/*3 = 0.041 mL/min/kg *2/*2, *2/*3, *3/*3 = 0.020 mg/min/kg •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD 50 Values Mouse: 3 mg/kg (Oral), 165 mg/kg (IV), 750 mg/kg (IP) Rat: 1.6 mg/kg (Oral), 320 mg/kg (Inhaled), 1400 mg/kg (Skin) Rabbit: 800 mg/kg (Oral) Pig: 1 mg/kg (Oral) Dog: 3 mg/kg (Oral) Cat: 6 mg/kg (Oral) Chicken: 942 mg/kg (Oral) Guinea Pig: 180 mg/kg (Oral) Overdose Doses of 1-2 mg/kg/day over a period of 15 days have been fatal in humans. Warfarin overdose is primarily associated with major bleeding particularly from the mucous membranes, gastrointestinal tract, and genitourinary system. Epistaxis, ecchymoses, as well as renal and hepatic bleeding are also associated. These symptoms become apparent within 2-4 days of overdose although increases in prothrombin time can be observed within 24 hours. Treatment for overdosed patients includes discontinuation of warfarin and administration of [vitamin K]. For more urgent reversal of anticoagulation prothrombin complex concentrate, blood plasma, or coagulation factor VIIa infusion can be used. Patients can be safely re-anticoagulated after reversal of the overdose. Carcinogenicity & Mutagenicity The carcinogenicity and mutagenicity of warfarin have not been thoroughly investigated. Reproductive Toxicity Warfarin is known to be a teratogen and its use during pregnancy is contraindicated in the absence of high thrombotic risk. Fetal warfarin syndrome, attributed to exposure during the 1st trimester, is characterized by nasal hypoplasia with or without stippled epiphyses, possible failure of nasal septum development, and low birth weight. Either dorsal midline dysplasia or ventral midline dysplasia can occur. Dorsal midline dysplasia includes agenisis of the corpus callosum, Dandy-Walker malformations, midline cerebellar hypoplasia. Ventral midline dysplasia is characterized by eye anomalies which can potentially include optic atrophy, blindness, and microphthalmia. Exposure during the 2nd and 3rd trimester is associated with hypoplasia of the extremities, developmental retardation, microcephaly, hydrocephaly, schizencephaly, seizures, scoliosis, deafness, congenital heart malformations, and fetal death. The critical exposure period is estimated to be week 6-9 based on case reports. Effects noted in the Canadian product monograph include developing a single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, polydactyl malformations, corneal leukoma, diaphragm hernia, and cleft palate. Lactation Official product monographs mention a study in 15 women. Warfarin was not detected in the breast milk of any woman and 6 infants were documented as having normal prothrombin times. The remaining 9 infants were not tested. Another study in 13 women using doses of 2-12 mg also revealed no detectable warfarin in breast milk. A woman who mistakenly took 25 mg of warfarin for 7 days while breastfeeding presented to an emergency room with an INR of 10 and prothrombin time of over 100 s. Her infant had a normal INR of 1.0 and prothrombin time of 10.3. The infant in this case has an increased prothrombin time of 33.8 s three weeks previous but this was judged not to be due to warfarin exposure. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Coumadin, Jantoven •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Coumafene Warfarin Warfarina Zoocoumarin •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Warfarin is a vitamin K antagonist used to treat venous thromboembolism, pulmonary embolism, thromboembolism with atrial fibrillation, thromboembolism with cardiac valve replacement, and thromboembolic events post myocardial infarction.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. The severity of the interaction is moderate.

Question: Does Bupropion and Warfarin interact? Information: •Drug A: Bupropion •Drug B: Warfarin •Severity: MODERATE •Description: Bupropion may decrease the excretion rate of Warfarin which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated for: 1) Prophylaxis and treatment of venous thromboembolism and related pulmonary embolism. 2) Prophylaxis and treatment of thromboembolism associated with atrial fibrillation. 3) Prophylaxis and treatment of thromboembolism associated with cardiac valve replacement. 4) Use as adjunct therapy to reduce mortality, recurrent myocardial infarction, and thromboembolic events post myocardial infarction. Off-label uses include: 1) Secondary prevention of stroke and transient ischemic attacks in patients with rheumatic mitral valve disease but without atrial fibrillation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Warfarin is an anticoagulant, as such it disrupts the coagulation cascade to reduce frequency and extent of thrombus formation. In patients with deep vein thrombosis or atrial fibrillation there is an increased risk of thrombus formation due to the reduced movement of blood. For patients with cardiac valve disease or valve replacements this increased coagulability is due to tissue damage. Thrombi due to venous thrombosis can travel to the lungs and become pulmonary emboli, blocking circulation to a portion of lung tissue. Thrombi which form in the heart can travel to the brain and cause ischemic strokes. Prevention of these events is the primary goal of warfarin therapy. Limitation of thrombus formation is also a source of adverse effects. In patients with atheroscelotic plaques rupture typically results in thrombus formation. When these patients are anticoagulated plaque rupture can allow the escape of cholesterol from the lipid core in the form of atheroemboli or cholesterol microemboli. These emboli are smaller than thrombi and block smaller vessels, usually less than 200 μm in diameter. The consequences of this are varied and depend on the location of the blockage. Effects include visual disturbances, acute kidney injury or worsening of chronic kidney disease, central nervous system ischemia, and purple or blue toe syndrome. Blue toe syndrome can be reversed if it has not progressed to tissue necrosis but the other effects of microemboli are often permanent. Antocoagulation appears to mediate warfarin-related nephropathy, a seemingly spontaneous kidney injury or worsening of chronic kidney disease associated with warfarin therapy. Nephropathy in this case appears to be due to increased passage of red blood cells through the glomerulus and subsequent blockage of renal tubules with red blood cell casts. This is worsened or possibly triggered by pre-existing kidney damage. Increased risk of warfarin-related nephropathy occurs at INRs over 3.0 but risk does not increase as a function of INR beyond this point. Warfarin has been linked to the development of calciphylaxis. This is thought to be due to warfarin's inhibition of vitamin K recycling as VKA is needed for the carboxylation of matrix Gla protein. This protein is an anti-calcification factor and its inhibition through preventing the carboxylation step in its production leads to a shift in calcification balance in favor of calciphylaxis. Tissue necrosis can occur early on in warfarin therapy. This is attributable to half lives of the clotting factors impacted by inhibition of vitamin K recycling. Proteins C and S are anticoagulation factors with half lives of 8 and 24 hours respectively. The coagulation factors IX, X, VII, and thrombin (factor II) have half lives of 24, 36, 6, and 50 hours respectively. This means proteins C and S are inactivated sooner than pro-coagulation proteins, with the exception of factor VII, resulting in a pro-thrombotic state for the first few days of therapy. Thrombi which form in this time period can occlude arterioles in various locations, blocking blood flow and causing tissue necrosis due to ischemia. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Warfarin is a [vitamin K] antagonist which acts to inhibit the production of vitamin K by vitamin K epoxide reductase. The reduced form of vitamin K, vitamin KH 2 is a cofactor used in the γ-carboxylation of coagulation factors VII, IX, X, and thrombin. Carboxylation induces a conformational change allowing the factors to bind Ca and to phospholipid surfaces. Uncarboxylated factors VII, IX, X, and thrombin are biologically inactive and therefore serve to interrupt the coagulation cascade. The endogenous anticoagulation proteins C and S also require γ-carboxylation to function. This is particularly true in the case of thrombin which must be activated in order to form a thrombus. vitamin KH 2 is converted to vitamin K epoxide as part of the γ-carboxylation reaction catalyzed by γ-glutamyl carboxylase. Vitamin K epoxide is then converted to vitamin K 1 by vitamin K epoxide reductase then back to vitamin KH 2 by vitamin K reductase. Warfarin binds to vitamin K epoxide reductase complex subunit 1 and irreversibly inhibits the enzyme thereby stopping the recycling of vitamin K by preventing the conversion of vitamin K epoxide to vitamin K 1. This process creates a hypercoagulable state for a short time as proteins C and S degrade first with half lives of 8 and 24 hours, with the exception of factor VII which has a half life of 6 hours. Factors IX, X, and finally thrombin degrade later with half lives of 24, 36, and 50 hours resulting in a dominant anticoagulation effect. In order to reverse this anticoagulation vitamin K must be supplied, either exogenously or by removal of the vitamin K epoxide reductase inhibition, and time allowed for new coagulation factors to be synthesized. It takes approximately 2 days for new coagulation factors to be synthesized in the liver. Vitamin K 2, functionally identical to vitamin K 1, is synthesized by gut bacteria leading to interactions with antibiotics as elimination of these bacteria can reduce vitamin K 2 16 •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Completely absorbed from the GI tract. The mean Tmax for warfarin sodium tablets is 4 hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vd of 0.14 L/kg. Warfarin has a distrubution phase lasting 6-12 hours. It is known to cross the placenta and achieves fetal serum concentrations similar to maternal concentrations. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 99% bound primarily to albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Metabolism of warfarin is both stereo- and regio-selective. The major metabolic pathway is oxidation to various hydroxywarfarins, comprising 80-85% of the total metabolites. CYP2C9 is the major enzyme catalyzing the 6- and 7-hydroxylation of S-warfarin while 4'-hydroxylation occurs through CYP2C18 with minor contributions from CYP2C19. R-warfarin is metabolized to 4'-hydroxywarfarin by CYP2C8 with some contirbuting by CYP2C19, 6- and 8-hydroxywarfarin by CYP1A2 and CYP2C19, 7-hydroxywarfarin by CYP1A2 and CYP2C8, and lastly to 10-hydroxywarfarin by CYP3A4. The 10-hydroxywarfarin metabolite as well as a benzylic alcohol metabolite undergo an elimination step to form dehydrowarfarin. The minor pathway of metabolism is the reduction of the ketone group to warfarin alcohols, comprising 20% of the metabolites. Limited conjugation occurs with sulfate and gluronic acid groups but these metabolites have only been confirmed for R-hydroxywarfarins. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): The elimination of warfarin is almost entirely by metabolism with a small amount excreted unchanged. 80% of the total dose is excreted in the urine with the remaining 20% appearing in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): R-warfarin is cleared more slowly than S-warfarin, at about half the rate. T 1/2 for R-warfarin is 37-89 hours. T 1/2 for S-warfarin is 21-43 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance of warfarin varies depending on CYP2C9 genotype. The *2 and *3 alleles appear in the Caucasian population at frequencies of 11% and 7% and are known to reduce clearance warfarin. Additional clearance reducing genotypes include the *5, *6, *9 and *11 alleles. Genotypes for which population clearance estimates have been found are listed below. *1/*1 = 0.065 mL/min/kg *1/*2, *1/*3 = 0.041 mL/min/kg *2/*2, *2/*3, *3/*3 = 0.020 mg/min/kg •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): LD 50 Values Mouse: 3 mg/kg (Oral), 165 mg/kg (IV), 750 mg/kg (IP) Rat: 1.6 mg/kg (Oral), 320 mg/kg (Inhaled), 1400 mg/kg (Skin) Rabbit: 800 mg/kg (Oral) Pig: 1 mg/kg (Oral) Dog: 3 mg/kg (Oral) Cat: 6 mg/kg (Oral) Chicken: 942 mg/kg (Oral) Guinea Pig: 180 mg/kg (Oral) Overdose Doses of 1-2 mg/kg/day over a period of 15 days have been fatal in humans. Warfarin overdose is primarily associated with major bleeding particularly from the mucous membranes, gastrointestinal tract, and genitourinary system. Epistaxis, ecchymoses, as well as renal and hepatic bleeding are also associated. These symptoms become apparent within 2-4 days of overdose although increases in prothrombin time can be observed within 24 hours. Treatment for overdosed patients includes discontinuation of warfarin and administration of [vitamin K]. For more urgent reversal of anticoagulation prothrombin complex concentrate, blood plasma, or coagulation factor VIIa infusion can be used. Patients can be safely re-anticoagulated after reversal of the overdose. Carcinogenicity & Mutagenicity The carcinogenicity and mutagenicity of warfarin have not been thoroughly investigated. Reproductive Toxicity Warfarin is known to be a teratogen and its use during pregnancy is contraindicated in the absence of high thrombotic risk. Fetal warfarin syndrome, attributed to exposure during the 1st trimester, is characterized by nasal hypoplasia with or without stippled epiphyses, possible failure of nasal septum development, and low birth weight. Either dorsal midline dysplasia or ventral midline dysplasia can occur. Dorsal midline dysplasia includes agenisis of the corpus callosum, Dandy-Walker malformations, midline cerebellar hypoplasia. Ventral midline dysplasia is characterized by eye anomalies which can potentially include optic atrophy, blindness, and microphthalmia. Exposure during the 2nd and 3rd trimester is associated with hypoplasia of the extremities, developmental retardation, microcephaly, hydrocephaly, schizencephaly, seizures, scoliosis, deafness, congenital heart malformations, and fetal death. The critical exposure period is estimated to be week 6-9 based on case reports. Effects noted in the Canadian product monograph include developing a single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, polydactyl malformations, corneal leukoma, diaphragm hernia, and cleft palate. Lactation Official product monographs mention a study in 15 women. Warfarin was not detected in the breast milk of any woman and 6 infants were documented as having normal prothrombin times. The remaining 9 infants were not tested. Another study in 13 women using doses of 2-12 mg also revealed no detectable warfarin in breast milk. A woman who mistakenly took 25 mg of warfarin for 7 days while breastfeeding presented to an emergency room with an INR of 10 and prothrombin time of over 100 s. Her infant had a normal INR of 1.0 and prothrombin time of 10.3. The infant in this case has an increased prothrombin time of 33.8 s three weeks previous but this was judged not to be due to warfarin exposure. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Coumadin, Jantoven •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Coumafene Warfarin Warfarina Zoocoumarin •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Warfarin is a vitamin K antagonist used to treat venous thromboembolism, pulmonary embolism, thromboembolism with atrial fibrillation, thromboembolism with cardiac valve replacement, and thromboembolic events post myocardial infarction. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The affected drug is a narrow therapeutic index drug that undergoes renal excretion as its main elimination pathway: a change in serum concentration may significantly elevate the risk of developing drug-related adverse effects. The severity of the interaction is moderate.

Does Bupropion and Yohimbine interact?

•Drug A: Bupropion •Drug B: Yohimbine •Severity: MAJOR •Description: The metabolism of Yohimbine can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated as a sympatholytic and mydriatic. Impotence has been successfully treated with yohimbine in male patients with vascular or diabetic origins and psychogenic origins. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Yohimbine is an indolalkylamine alkaloid with chemical similarity to reserpine. Yohimbine blocks presynaptic alpha-2 adrenergic receptors. Its action on peripheral blood vessels resembles that of reserpine, though it is weaker and of short duration. Yohimbine's peripheral autonomic nervous system effect is to increase parasympathetic (cholinergic) and decrease sympathetic (adrenergic) activity. It is to be noted that in male sexual performance, erection is linked to cholinergic activity and to alpha-2 adrenergic blockade which may theoretically result in increased penile inflow, decreased penile outflow or both. Yohimbine exerts a stimulating action on the mood and may increase anxiety. Such actions have not been adequately studied or related to dosage although they appear to require high doses of the drug. Yohimbine has a mild anti-diuretic action, probably via stimulation of hypothalmic center and release of posterior pituitary hormone. Reportedly Yohimbine exerts no significant influence on cardiac stimulation and other effects mediated by (beta)-adrenergic receptors. Its effect on blood pressure, if any, would be to lower it; however, no adequate studies are at hand to quantitate this effect in terms of Yohimbine dosage. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Yohimbine is a pre-synaptic alpha 2-adrenergic blocking agent. The exact mechanism for its use in impotence has not been fully elucidated. However, yohimbine may exert its beneficial effect on erectile ability through blockade of central alpha 2-adrenergic receptors producing an increase in sympathetic drive secondary to an increase in norepinephrine release and in firing rate of cells in the brain noradrenergic nuclei. Yohimbine-mediated norepinephrine release at the level of the corporeal tissues may also be involved. In addition, beneficial effects may involve other neurotransmitters such as dopamine and serotonin and cholinergic receptors. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed following oral administration. Bioavailability is highly variable, ranging from 7 to 87% (mean 33%). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Yohimbine appears to undergo extensive metabolism in an organ of high flow such as the liver or kidney, however, the precise metabolic fate of yohimbine has not been fully determined. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): Elimination half-life is approximately 36 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Johimbin Quebrachin Yohimbic acid methyl ester Yohimbin Yohimbine Yohimbinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Yohimbine is an alpha-2-adrenergic blocker and sympatholytic found in supplements used to.

The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Yohimbine interact? Information: •Drug A: Bupropion •Drug B: Yohimbine •Severity: MAJOR •Description: The metabolism of Yohimbine can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Indicated as a sympatholytic and mydriatic. Impotence has been successfully treated with yohimbine in male patients with vascular or diabetic origins and psychogenic origins. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Yohimbine is an indolalkylamine alkaloid with chemical similarity to reserpine. Yohimbine blocks presynaptic alpha-2 adrenergic receptors. Its action on peripheral blood vessels resembles that of reserpine, though it is weaker and of short duration. Yohimbine's peripheral autonomic nervous system effect is to increase parasympathetic (cholinergic) and decrease sympathetic (adrenergic) activity. It is to be noted that in male sexual performance, erection is linked to cholinergic activity and to alpha-2 adrenergic blockade which may theoretically result in increased penile inflow, decreased penile outflow or both. Yohimbine exerts a stimulating action on the mood and may increase anxiety. Such actions have not been adequately studied or related to dosage although they appear to require high doses of the drug. Yohimbine has a mild anti-diuretic action, probably via stimulation of hypothalmic center and release of posterior pituitary hormone. Reportedly Yohimbine exerts no significant influence on cardiac stimulation and other effects mediated by (beta)-adrenergic receptors. Its effect on blood pressure, if any, would be to lower it; however, no adequate studies are at hand to quantitate this effect in terms of Yohimbine dosage. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Yohimbine is a pre-synaptic alpha 2-adrenergic blocking agent. The exact mechanism for its use in impotence has not been fully elucidated. However, yohimbine may exert its beneficial effect on erectile ability through blockade of central alpha 2-adrenergic receptors producing an increase in sympathetic drive secondary to an increase in norepinephrine release and in firing rate of cells in the brain noradrenergic nuclei. Yohimbine-mediated norepinephrine release at the level of the corporeal tissues may also be involved. In addition, beneficial effects may involve other neurotransmitters such as dopamine and serotonin and cholinergic receptors. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed following oral administration. Bioavailability is highly variable, ranging from 7 to 87% (mean 33%). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Yohimbine appears to undergo extensive metabolism in an organ of high flow such as the liver or kidney, however, the precise metabolic fate of yohimbine has not been fully determined. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): Elimination half-life is approximately 36 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Johimbin Quebrachin Yohimbic acid methyl ester Yohimbin Yohimbine Yohimbinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Yohimbine is an alpha-2-adrenergic blocker and sympatholytic found in supplements used to. Output: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Zafirlukast interact?

•Drug A: Bupropion •Drug B: Zafirlukast •Severity: MODERATE •Description: The metabolism of Bupropion can be decreased when combined with Zafirlukast. •Extended Description: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the prophylaxis and chronic treatment of asthma. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA) indicated for the prophylaxis and chronic treatment of asthma. Patients with asthma were found in one study to be 25-100 times more sensitive to the bronchoconstricting activity of inhaled LTD 4 than nonasthmatic subjects. In vitro studies demonstrated that zafirlukast antagonized the contractile activity of three leukotrienes (LTC 4, LTD 4 and LTE 4 ) in conducting airway smooth muscle from laboratory animals and humans. Zafirlukast prevented intradermal LTD 4 -induced increases in cutaneous vascular permeability and inhibited inhaled LTD 4 -induced influx of eosinophils into animal lungs. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zafirlukast is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD 4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed following oral administration, reduced following a high-fat or high-protein meal. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 70 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 99% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): The most common metabolic products are hydroxylated metabolites which are excreted in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): 10 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): apparent oral CL=20 L/h 11.4 L/h [7-11 yrs] 9.2 L/h [5-6 yrs] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Side effects include rash and upset stomach. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Accolate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zafirlukast •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zafirlukast is a leukotriene receptor antagonist used for prophylaxis and chronic treatment of asthma.

The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is moderate.

Question: Does Bupropion and Zafirlukast interact? Information: •Drug A: Bupropion •Drug B: Zafirlukast •Severity: MODERATE •Description: The metabolism of Bupropion can be decreased when combined with Zafirlukast. •Extended Description: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the prophylaxis and chronic treatment of asthma. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA) indicated for the prophylaxis and chronic treatment of asthma. Patients with asthma were found in one study to be 25-100 times more sensitive to the bronchoconstricting activity of inhaled LTD 4 than nonasthmatic subjects. In vitro studies demonstrated that zafirlukast antagonized the contractile activity of three leukotrienes (LTC 4, LTD 4 and LTE 4 ) in conducting airway smooth muscle from laboratory animals and humans. Zafirlukast prevented intradermal LTD 4 -induced increases in cutaneous vascular permeability and inhibited inhaled LTD 4 -induced influx of eosinophils into animal lungs. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zafirlukast is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD 4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed following oral administration, reduced following a high-fat or high-protein meal. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 70 L •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 99% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): The most common metabolic products are hydroxylated metabolites which are excreted in the feces. •Half-life (Drug A): 24 hours •Half-life (Drug B): 10 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): apparent oral CL=20 L/h 11.4 L/h [7-11 yrs] 9.2 L/h [5-6 yrs] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Side effects include rash and upset stomach. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Accolate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zafirlukast •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zafirlukast is a leukotriene receptor antagonist used for prophylaxis and chronic treatment of asthma. Output: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is moderate.

Does Bupropion and Zaleplon interact?

•Drug A: Bupropion •Drug B: Zaleplon •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Zaleplon is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of short-term treatment of insomnia in adults. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zaleplon is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class and is indicated for the short-term treatment of insomnia. While Zaleplon is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABA B Z) receptor complex. Subunit modulation of the GABA B Z receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. Zaleplon also binds selectively to the CNS GABA A -receptor chloride ionophore complex at benzodiazepine(BZ) omega-1 (BZ1, ο1) receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zaleplon exerts its action through subunit modulation of the GABA B Z receptor chloride channel macromolecular complex. Zaleplon also binds selectively to the brain omega-1 receptor located on the alpha subunit of the GABA-A/chloride ion channel receptor complex and potentiates t-butyl-bicyclophosphorothionate (TBPS) binding. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Absorption Zaleplon is rapidly and almost completely absorbed following oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 1.4 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 60% (in vitro plasma protein binding). •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zaleplon is primarily metabolized by aldehyde oxidase. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. After oral administration, zaleplon is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. Renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): Approximately 1 hour •Clearance (Drug A): No clearance available •Clearance (Drug B): 1 L/h/kg •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Side effects include abdominal pain, amnesia, dizziness, drowsiness, eye pain, headache, memory loss, menstrual pain, nausea, sleepiness, tingling, weakness •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Sonata •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zaleplon •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zaleplon is a sedative used for short term treatment of insomnia in adults.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Zaleplon interact? Information: •Drug A: Bupropion •Drug B: Zaleplon •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Zaleplon is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the treatment of short-term treatment of insomnia in adults. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zaleplon is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class and is indicated for the short-term treatment of insomnia. While Zaleplon is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABA B Z) receptor complex. Subunit modulation of the GABA B Z receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. Zaleplon also binds selectively to the CNS GABA A -receptor chloride ionophore complex at benzodiazepine(BZ) omega-1 (BZ1, ο1) receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zaleplon exerts its action through subunit modulation of the GABA B Z receptor chloride channel macromolecular complex. Zaleplon also binds selectively to the brain omega-1 receptor located on the alpha subunit of the GABA-A/chloride ion channel receptor complex and potentiates t-butyl-bicyclophosphorothionate (TBPS) binding. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Absorption Zaleplon is rapidly and almost completely absorbed following oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 1.4 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 60% (in vitro plasma protein binding). •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zaleplon is primarily metabolized by aldehyde oxidase. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. After oral administration, zaleplon is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. Renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): Approximately 1 hour •Clearance (Drug A): No clearance available •Clearance (Drug B): 1 L/h/kg •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Side effects include abdominal pain, amnesia, dizziness, drowsiness, eye pain, headache, memory loss, menstrual pain, nausea, sleepiness, tingling, weakness •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Sonata •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zaleplon •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zaleplon is a sedative used for short term treatment of insomnia in adults. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.