Pharmacodynamics +<unk>  Site Ki (nM) Action Species Ref >1,000 >1,000 5-HT1A 6.75 Partial agonist Rat 5-HT2A 2.03 Antagonist Rat 5-HT2B 5-HT2C 415 Pig 5-HT3 >1,000 5-HT4 >1,000 5-HT7 0.495 Antagonist Human α1 47.9 Rat α2A 40.7 Human α2B α2C 10.8 Antagonist Human β1 >1,000 β2 >1,000 D1 262 D2 1.68 Antagonist Rat D3 15.7 Antagonist D4.4 30 D5 H1 >1,000 Guinea pig M1 >1,000 Human Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.<unk>  acts as an antagonist of the dopamine D2 and D3 receptors, the serotonin 5-HT2A and 5-HT7 receptors, and the α2C-adrenergic receptor, and as a partial agonist of the serotonin 5-HT1A receptor. It has only low and likely clinically unimportant affinity for the serotonin 5-HT2C receptor, which may underlie its low propensity for appetite stimulation and weight gain. The drug also has negligible affinity for the histamine H1 receptor and the muscarinic acetylcholine receptors, and hence has no antihistamine or anticholinergic effects. Pharmacokinetics ID-14283, the main active metabolite. The hydroxylation of the norbornane ring is highlighted. The other active metabolite, ID-14326, has the OH group in endo position. The main inactivation step by oxidative N-dealkylation produces the metabolites ID-11614 and ID-20219.<unk>  is taken by mouth and has an estimated absorption rate of 9 to 19%. Studies have shown that when<unk>  is taken with food, absorption increases about twofold. Peak blood plasma concentrations are reached after one to three hours. About 99% of the circulating substance are bound to plasma proteins.<unk>  is mainly metabolized in the liver via the enzyme CYP3A4, but has negligible affinity to other cytochrome P450 enzymes. It is transported by P-glycoprotein and ABCG2 and also inhibits these carrier proteins in vitro. It also inhibits the solute carrier protein SLC22A1, but no other relevant transporters. Main metabolism pathways are oxidative N-dealkylation between the piperazine and cyclohexane rings, hydroxylation of the norbornane ring, and S-oxidation.:59 Other pathways are hydroxylation of the cyclohexane ring and reductive cleavage of the isothiazole ring followed by S-methylation. The two relevant active metabolites are the norbornane hydroxylation products called ID-14283 and ID-14326, the former reaching pharmacologically relevant blood plasma concentrations. The two major inactive metabolites are the N-dealkylation products (the carboxylic acid ID-20219 and the piperazine ID-11614), and a norbornane hydroxylated derivative of ID-20219 (ID-20220). Of<unk>  and its metabolites circulating in the blood, the native drug makes up 11%, the main active metabolite 4%, and the inactive carboxylic acids 24% and 11%, respectively. Several dozen metabolites have been identified altogether.:59–61 Biological half-life is given as 18 hours or 20 to 40 hours in different sources. 80% or 67% of a radiolabelled dose was recovered from the faeces, and 9% or 19% from the urine.
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