Pharmacodynamics +<unk>  (and metabolite) Site<unk>  Species Ref 160–>10,000 202–432 Human ≥8,500 ≥1,940 Human ≥7,400 Human 5-HT1A 96–118 44–400 Human 5-HT1B >10,000 89–501 Human 5-HT1D 106 210–1,300 Human 5-HT1E >10,000 Human 5-HT1F 5-HT2A 20–45 32–398 Human 5-HT2B 74–189 3.2–63 Human 5-HT2C 224–402 3.4–251 Human 5-HT3 >10,000 427 Human 5-HT4 5-HT5A >10,000 1,354 Human 5-HT6 >10,000 1,748 Human 5-HT7 1,782 163 Human α1 12–42 97–2,900 Human α1A 153 1,386 Human α1B 915 Human α1D α2 106–490 112–570 Human α2A 728 145 Human α2B 106 Human α2C 155 124 Human β >10,000 2,500 Human β1 >10,000 2,359 Human β2 >10,000 3,474 Human D1 3,730 7,000 Human D2 ≥3,500 >10,000 Human D3 353 >10,000 Rat D4 703 Human D5 >10,000 >10,000 Human H1 220–1,100 326 Human H2 3,290 Human H3 >10,000 Guinea pig H4 >10,000 Human >10,000 >10,000 Human >10,000 >10,000 Human σ1 >10,000 Rat σ2 536 8,350 Rat I1 759 Rat (MK-801) >10,000 Rat >10,000 6,043 Rat Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.<unk>  is a mixed agonist and antagonist of various serotonin receptors, antagonist of adrenergic receptors, weak histamine H1 receptor antagonist, and weak serotonin reuptake inhibitor. More specifically, it is an antagonist of 5-HT2A and 5-HT2B receptors, a partial agonist of the 5-HT1A receptor, and an antagonist of the α1- and α2-adrenergic receptors. It is also a ligand of the 5-HT2C receptor with lower affinity than for the 5-HT2A receptor. However, it is unknown whether<unk>  acts as a full agonist, partial agonist, or antagonist of the 5-HT2C receptor.<unk>  is a 5-HT1A receptor partial agonist similarly to buspirone and tandospirone but with comparatively greater intrinsic activity. A range of weak affinities (Ki) have been reported for<unk>  at the human histamine H1 receptor, including 220nM, 350nM, 500nM, and 1,100nM.<unk>  has a minor active metabolite known as meta-chlorophenylpiperazine (mCPP), and this metabolite may contribute to some degree to the pharmacological properties of<unk> . In contrast to<unk> , mCPP is an agonist of various serotonin receptors. It has relatively low affinity for α1-adrenergic receptors unlike<unk> , but does high affinity for α2-adrenergic receptors and weak affinity for the H1 receptor. In addition to direct interactions with serotonin receptors, mCPP is a serotonin releasing agent similarly to agents like fenfluramine and MDMA. In contrast to these serotonin releasing agents however, mCPP does not appear to cause long-term serotonin depletion (a property thought to be related to serotonergic neurotoxicity).<unk> 's 5-HT2A receptor antagonism and weak serotonin reuptake inhibition form the basis of its common label as an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) type. Target occupancy studies Studies have estimated occupancy of target sites by<unk>  based on<unk>  concentrations in blood and brain and on the affinities of<unk>  for the human targets in question. Roughly half of brain 5-HT2A receptors are blocked by 1mg of<unk>  and essentially all 5-HT2A receptors are saturated at 10mg of<unk> , but the clinically effective hypnotic doses of<unk>  are in the 25–100mg range. The occupancy of the serotonin transporter (SERT) by<unk>  is estimated to be 86% at 100mg/day and 90% at 150mg/day.<unk>  may almost completely occupy the 5-HT2A and 5-HT2C receptors at doses of 100 to 150mg/day. Significant occupancy of a number of other sites may also occur. However, another study estimated much lower occupancy of the SERT and 5-HT2A receptors by<unk> . + Estimated occupancy of biological targets by<unk>  at different doses Target Estimated target occupancy 50mg/day 100mg/day 150mg/day SERT 75% 86% 90% 5-HT1A 91% 95% 97% 5-HT1D 91% 95% 97% 5-HT2A 97% 98% 99% 5-HT2B 94% 97% 98% 5-HT2C 83% 91% 94% 5-HT7 39% 56% 66% α1A 88% 94% 96% α2A 61% 75% 82% α2C 88% 94% 96% D4 62% 76% 83% H1 84% 91% 94% Very low (1B, 5-HT1E, 5-HT3, 5-HT5A, 5-HT6, β1, β2, D5, H4, mAChRs, nAChRs. Low (1, D2. Not determined: α1B, α2B, D3. Note: Another study estimated much lower occupancies. Correspondence to clinical effects<unk>  may act predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression. Its inhibitory effects on serotonin reuptake and 5-HT2C receptors are comparatively weak. In relation to these properties,<unk>  does not have similar properties to selective serotonin reuptake inhibitors (SSRIs) and is not particularly associated with increased appetite and weight gain—unlike other 5-HT2C antagonists like mirtazapine. Moderate 5-HT1A partial agonism may contribute to<unk> 's antidepressant and anxiolytic actions to some extent as well. The combined actions of 5-HT2A and 5HT2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of<unk> . Doses of<unk>  lower than those effective for antidepressant action are frequently used for the effective treatment of insomnia. Low doses exploit<unk> 's potent actions as a 5-HT2A receptor antagonist, and its properties as an antagonist of H1 and α1-adrenergic receptors, but do not adequately exploit its SERT or 5-HT2C inhibition properties, which are weaker. Since insomnia is one of the most frequent residual symptoms of depression after treatment with an SSRI, a hypnotic is often necessary for patients with a major depressive episode. Not only can a hypnotic potentially relieve the insomnia itself, but treating insomnia in patients with major depression may also increase remission rates due to improvement of other symptoms such as loss of energy and depressed mood. Thus, the ability of low doses of<unk>  to improve sleep in depressed patients may be an important mechanism whereby<unk>  can augment the efficacy of other antidepressants.<unk> 's potent α1-adrenergic blockade may cause some side effects like orthostatic hypotension and sedation. Conversely, along with 5-HT2A and H1 receptor antagonism, it may contribute to its efficacy as a hypnotic.<unk>  lacks any affinity for the muscarinic acetylcholine receptors, so does not produce anticholinergic side effects. mCPP, a non-selective serotonin receptor modulator and serotonin releasing agent, is an active metabolite of<unk>  and has been suggested to possibly play a role in its therapeutic benefits. However, research has not supported this hypothesis and mCPP might actually antagonize the efficacy of<unk>  as well as produce additional side effects. Pharmacokinetics Absorption<unk>  is well-absorbed after oral administration. Its bioavailability is 65 to 80%. Peak blood levels of<unk>  occur 1 to 2hours after ingestion and peak levels of the metabolite mCPP occur after 2 to 4hours. Absorption is somewhat delayed and enhanced by food. Distribution<unk>  is not sequestered into any tissue. The medication is 89 to 95% protein-bound. The volume of distribution of<unk>  is 0.8 to 1.5L/kg.<unk>  is highly lipophilic. Metabolism The metabolic pathways involved in the metabolism are not well-characterized. In any case, the cytochrome P450 enzymes CYP3A4, CYP2D6, and CYP1A2 may all be involved to varying extents.<unk>  is known to be extensively metabolized by the liver via hydroxylation, N-oxidation, and N-dealkylation. Several metabolites of<unk>  have been identified, including a dihydrodiol metabolite (via hydroxylation), a metabolite hydroxylated at the para position of the meta-chlorophenyl ring (via CYP2D6), oxotriazolepyridinepropionic acid (TPA) and mCPP (both via N-dealkylation of the piperazinyl nitrogen mediated by CYP3A4), and a metabolite formed by N-oxidation of the piperazinyl nitrogen. CYP1A2, CYP2D6, and CYP3A4 genotypes all do not seem to predict concentrations of<unk>  or mCPP. In any case, there are large interindividual variations in the metabolism of<unk> . In addition, poor metabolizers of dextromethorphan, a CYP2D6 substrate, eliminate mCPP more slowly and have higher concentrations of mCPP than do extensive metabolizers. mCPP is formed from<unk>  by CYP3A4 and is metabolized via hydroxylation by CYP2D6 (to a para-hydroxylated metabolite). It may contribute to the pharmacological actions of<unk> . mCPP levels are only 10% of those of<unk>  during therapy with<unk> , but is nonetheless present at concentrations known to produce psychic and physical effects in humans when mCPP has been administered alone. In any case, the actions of<unk> , such as its serotonin antagonism, might partially overwhelm those of mCPP. As a consequence of the production of mCPP as a metabolite, patients administered<unk>  may test positive on EMIT II urine tests for the presence of MDMA ("ecstasy"). Elimination The elimination of<unk>  is biphasic: the first phase's half-life (distribution) is 3 to 6hours, and the following phase's half-life (elimination) is 4.1 to 14.6hours. The elimination half-life of extended-release<unk>  is 9.1 to 13.2hours. The elimination half-life of mCPP is 2.6 to 16.0hours and is longer than that of<unk> . Metabolites are conjugated to gluconic acid or glutathione and around 70 to 75% of 14C-labelled<unk>  was found to be excreted in the urine within 72hours. The remaining drug and its metabolites are excreted in the faeces via biliary elimination. Less than 1% of the drug is excreted in its unchanged form. After an oral dose of<unk> , it was found to be excreted 20% in the urine as TPA and conjugates, 9% as the dihydrodiol metabolite, and less than 1% as unconjugated mCPP. mCPP is glucuronidated and sulfated similarly to other<unk>  metabolites.
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