title: Mechanism-based inhibition of human cytochrome P450 2B6 by ticlopidine, clopidogrel, and the thiolactone metabolite of prasugrel.
abstract: Mechanism-based inhibition of CYP2B6 in human liver microsomes by thienopyridine antiplatelet agents ticlopidine and clopidogrel and the thiolactone metabolites of those two agents plus that of prasugrel were investigated by determining the time- and concentration-dependent inhibition of the activity of bupropion hydroxylase as the typical CYP2B6 activity. By comparing the ratios of k(inact) (maximal inactivation rate constant)/K(I) (the inactivator concentration producing a half-maximal rate of inactivation), it was found that the thiolactone metabolite of prasugrel is 10- and 22-fold less potent, respectively, in the mechanism-based inhibition of CYP2B6 than ticlopidine and clopidogrel. The k(inact)/K(I) ratio of the thiolactone metabolite of ticlopidine was comparable with that of the parent compound, whereas this ratio for the thiolactone metabolite of clopidogrel was significantly smaller than that of clopidogrel. In conclusion, ticlopidine, its thiolactone metabolite, and clopidogrel were more potent mechanism-based inhibitors of CYP2B6 than the thiolactone metabolite of prasugrel.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710, Japan. nishiya.yumi.m4@daiichisankyo.co.jp
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nishiya
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Hagihara
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.forename: Masami
authors.initials: M
authors.lastname: Tajima
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Miura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurihara
authors.forename: Nagy A
authors.initials: NA
authors.lastname: Farid
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ikeda
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D000077144:Clopidogrel; D065702:Cytochrome P-450 CYP2B6; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D007783:Lactones; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine