Pharmacodynamics + Molecular targets of<unk>  Site Ki (nM) Species References 0.15–3.3 Human 420–925 Human 22–315 Human 5-HT1A >35,000 Human 5-HT2A 2,207 Rat 5-HT2C 2,298 Pig α1A 1900 Human α1B 3,500 Human α1D 2,500 Human α2 477–4,100 Human D2 10,700 Human H1 24,000 Human 427–2,100 Human σ1 32–57 Rat σ2 5,297 Rat Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to or inhibits the site.<unk>  is a selective<unk> otonin reuptake inhibitor (SSRI). By binding<unk> otonin transporter <unk> T) it inhibits neuronal reuptake of<unk> otonin and potentiates<unk> otonergic activity in the central nervous system. It does not significantly affect norepinephrine transporter (NET),<unk> otonin, dopamine, adrenergic, histamine, acetylcholine, GABA or benzodiazepine receptors.<unk>  also shows relatively high activity as an inhibitor of the dopamine transporter (DAT) and antagonist of the sigma σ1 receptor (but not the σ2 receptor). However,<unk>  affinity for its main target <unk> T) is much greater than its affinity for σ1 receptor and DAT. Although there could be a role for the σ1 receptor in the pharmacology of<unk> , the significance of this receptor in its actions is unclear. Similarly, the clinical relevance of<unk> 's blockade of the dopamine transporter is uncertain. Pharmacokinetics Desmethylsertraline, the major metabolite of<unk> . Absorption Following a single oral dose of<unk> , mean peak blood levels of<unk>  occur between 4.5 to 8.4 hours. Bioavailability is likely linear and dose-proportional over a dose range of 150 to 200 mg. Concomitant intake of<unk>  with food slightly increases<unk>  peak levels and total exposure. There is an approximate 2-fold accumulation of<unk>  with continuous administration and steady-state levels are reached within one week. Distribution<unk>  is highly plasma protein bound (98.5%) across a concentration range of 20 to 500 ng/mL. Despite the high plasma protein binding,<unk>  and its metabolite desmethylsertraline at respective tested concentrations of 300 ng/mL and 200 ng/mL were found not to interfere with the plasma protein binding of warfarin and propranolol, two other highly plasma protein-bound drugs. Metabolism<unk>  is subject to extensive first-pass metabolism, as indicated by a small study of radiolabeled<unk>  in which less than 5% of plasma radioactivity was unchanged<unk>  in two males. The principal metabolic pathway for<unk>  is N-demethylation into desmethylsertraline (N-desmethylsertraline) mainly by CYP2B6. Reduction, hydroxylation, and glucuronide conjugation of both<unk>  and desmethylsertraline also occur. Desmethylsertraline, while pharmacologically active, is substantially (50-fold) weaker than<unk>  as a<unk> otonin reuptake inhibitor and its influence on the clinical effects of<unk>  is thought to be negligible. Based on in vitro studies,<unk>  is metabolized by multiple cytochrome 450 isoforms; however, it appears that in the human body CYP2C19 plays the most important role, followed by CYP2B6. In addition to the cytochrome P450 system,<unk>  can be oxidatively deaminated in vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo. Elimination The elimination half-life of<unk>  is on average 26 hours, with a range of 13 to 45 hours. The half-life of<unk>  is longer in women (32 hours) than in men (22 hours), which leads to 1.5-fold higher exposure to<unk>  in women compared to men. The elimination half-life of desmethylsertraline is 62 to 104 hours. In a small study of two males,<unk>  was excreted to similar degrees in urine and feces (40 to 45% each within 9 days). Unchanged<unk>  was not detectable in urine, whereas 12 to 14% unchanged<unk>  was present in feces. Pharmacogenomics CYP2C19 and CYP2B6 are thought to be the key cytochrome P450 enzymes involved in the metabolism of<unk> . Relative to CYP2C19 normal (extensive) metabolizers, poor metabolizers have 2.7-fold higher levels of<unk>  and intermediate metabolizers have 1.4-fold higher levels. In contrast, CYP2B6 poor metabolizers have 1.6-fold higher levels of<unk>  and intermediate metabolizers have 1.2-fold higher levels.
Sertraline
Citalopram
Escitalopram
Clomipramine
Trimipramine
Mirtazapine
Asenapine
Quetiapine