+Pharmacology of<unk>  and its metabolites.<unk>  R,R-Hydroxybupropion S,S-Hydroxybupropion Threo-hydrobupropion Erythro-hydrobupropion Exposure and half-life AUC relativeto<unk>  1 23.8 0.6 11.2 2.5 Half-life 11 h 19 h 15 h 31 h 22 h Inhibition IC50 (μM) in human cells, unless noted otherwise DAT, uptake 0.66 inactive 0.63 47 (rat) no data NET, uptake 1.85 9.9 0.24 16 (rat) no data SERT, uptake inactive inactive inactive 67 (rat) no data αβ nicotinic 1.8 6.5 11 14 (rat) no data αβ nicotinic 12 31 3.3 no data no data αβγδ nicotinic 7.9 7.6 28 no data no data Pharmacodynamics and mechanism of action The mechanism of action of<unk>  is unclear but believed to be related to the fact that<unk>  is a norepinephrine–dopamine reuptake inhibitor (NDRI) and antagonist of several nicotinic acetylcholine receptors. It is uncertain if it is a norepinephrine–dopamine releasing agent. Pharmacological actions of<unk> , to a significant degree, are due to its active metabolites hydroxybupropion, threo-hydrobupropion, and erythro-hydrobupropion that are present in the blood plasma at comparable or higher levels. Overall action of these metabolites, and particularly one enantiomer S,S-hydroxybupropion, is also characterized by inhibition of norepinephrine and dopamine reuptake and nicotinic antagonism (see the chart on the right).<unk>  has no meaningful direct activity at a variety of receptors, including α- and β-adrenergic, dopamine, serotonin, histamine, and muscarinic acetylcholine receptors. The occupancy of dopamine transporter (DAT) by<unk>  (300 mg/day) and its metabolites in the human brain as measured by several positron emission tomography (PET) studies is approximately 20%, with a mean occupancy range of about 14 to 26%. For comparison, the NDRI methylphenidate at therapeutic doses is thought to occupy greater than 50% of DAT sites. In accordance with its low DAT occupancy, no measurable dopamine release in the human brain was detected with<unk>  (150 mg/day) in a PET study. These findings raise questions about the role of dopamine reuptake inhibition in the pharmacology of<unk> , and suggest that other actions may be responsible for its therapeutic effects. More research is needed in this area. No data are available on occupancy of the norepinephrine transporter (NET) by<unk>  and its metabolites. However, due to the increased exposure of hydroxybupropion over<unk>  itself, which has higher affinity to NET than DAT (R,R- has no DAT affinity at all, and S,S- has ~3x higher affinity to NET over DAT),<unk> 's overall pharmacological profile in humans may end up making it effectively more of an NRI than a DRI. Pharmacokinetics Principal pathways of<unk>  metabolism. After oral administration,<unk>  is rapidly and completely absorbed reaching the peak blood plasma concentration after 1.5 hours (tmax). Sustained release (SR) and extended release (XL) formulations have been designed to slow down absorption resulting in tmax of 3 hours and 5 hours, respectively. Absolute bioavailability of<unk>  is unknown but is presumed to be low, at 5–20%, due to the first-pass metabolism. As for the relative biovailability of the formulations, XL formulation has lower bioavailability (68%) compared to SR formulation and immediate release<unk> .<unk>  is metabolized in the body by a variety of pathways. The oxidative pathways are by cytochrome P450 isoenzymes CYP2B6 leading to R,R- and S,S-hydroxybupropion and, to a lesser degree, CYP2C19 leading to 4'-hydroxybupropion. The reductive pathways are by 11β-hydroxysteroid dehydrogenase type 1 in the liver and AKR7A2/AKR7A3 in the intestine leading to threo-hydrobupropion and by yet unknown enzyme leading to erythro-hydrobupropion. (see Scheme on the right) The metabolism of<unk>  is highly variable: the effective doses of<unk>  received by persons who ingest the same amount of the drug may differ by as much as 5.5 times (with a half-life of 12–30 hours), while the effective doses of hydroxybupropion may differ by as much as 7.5 times (with a half-life of 15–25 hours). Based on this, some researchers have advocated monitoring of the blood level of<unk>  and hydroxybupropion.
Bupropion
Atomoxetine
Hydroxybupropion
Entropion
Citalopram
Duloxetine
Dapoxetine
Fluoxetine