[Pharmacokinetics of zotepine and various factors affecting that of zotepine].
The single dose kinetics of zotepine, and effects of smoking and cytochrome P450 2C19 (CYP2C19) on the kinetics, together with pharmacokinetic interaction between zotepine and diazepam were investigated. 1) The pharmacokinetics of zotepine was investigated in 14 healthy volunteers, and was compared between 7 extensive metabolizers (EM) and 7 poor metabolizers (PM) of CYP2C19 or between 8 smokers (S) and 6 non-smokers (NS). 2) In 17 patients treated with zotepine alone, intraindividual changes in the plasma concentrations of zotepine before and after coadministration of diazepam were examined. The time of the maximal plasma concentration and the elimination half-life of zotepine in 14 volunteers were about 4 hours and 21 hours, respectively, which were found to be much longer than previously reported data. There were no significant differences in the pharmacokinetic parameters between the EM and PM groups or between the S and NS groups. The plasma concentrations of zotepine were significantly increased after coadministration of diazepam. Consequently, it is suggested that smoking does not affect the pharmacokinetics and metabolism of zotepine, and that the metabolism of zotepine is not mediated by CYP2C19. Elevation in the plasma concentrations of zotepine after coadministration of diazepam may be caused by the inhibitory effect of diazepam on zotepine metabolism. As a plausible explanation for this, the metabolism of zotepine and diazepam may be commonly mediated not by CYP2C19 but by cytochrome P450 3A4, and the pharmacokinetic interactions may result from competitive inhibition between these two drugs.
Department of Neuropsychiatry, Hirosaki University School of Medicine, Japan.
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Tanaka
D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology; D003988:Dibenzothiepins / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000502:physiology; D012907:Smoking
D014150:Antipsychotic Agents; D003988:Dibenzothiepins; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D003975:Diazepam; C022172:zotepine