RT Journal Article SR Electronic T1 Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 589 OP 593 DO 10.1124/dmd.108.022988 VO 37 IS 3 A1 Yumi Nishiya A1 Katsunobu Hagihara A1 Takashi Ito A1 Masami Tajima A1 Shin-ichi Miura A1 Atsushi Kurihara A1 Nagy A. Farid A1 Toshihiko Ikeda YR 2009 UL http://dmd.aspetjournals.org/content/37/3/589.abstract AB 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 kinact (maximal inactivation rate constant)/KI (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 kinact/KI 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. The American Society for Pharmacology and Experimental Therapeutics