Comparison of human cytochrome P450 inhibition by the thienopyridines prasugrel, clopidogrel, and ticlopidine.
Differences in the inhibition of cytochrome P450 activities among thienopyridine antiplatelet agents, ticlopidine, clopidogrel, prasugrel, and the metabolites, 2-oxo-clopidogrel, clopidogrel acid metabolite, deacetylated metabolite of prasugrel (R-95913) and the pharmacologically active metabolites of clopidogrel and prasugrel, were examined using recombinant cytochromes P450 and fluorescent probe substrates. Ticlopidine and clopidogrel inhibited CYP2B6 with IC(50) values of 0.0517+/-0.0323 microM and 0.0182+/-0.0069 microM, respectively, and inhibited CYP2C19 with IC(50) values of 0.203+/-0.124 microM and 0.524+/-0.160 microM, respectively. Ticlopidine also inhibited CYP2D6 (IC(50) of 0.354+/-0.158 microM). In contrast, 2-oxo-clopidogrel, prasugrel and R-95913 were much weaker inhibitors of CYP2B6, CYP2C19 and CYP2D6. The inhibitory effects of all the compounds tested were much weaker on the isoforms other than those indicated above. The active metabolites of clopidogrel and prasugrel and clopidogrel acid metabolite also did not affect the activities of the P450s examined.
Hagihara
Katsunobu
K
Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Japan. hagihara.katsunobu.fc@daiichisankyo.co.jp
Nishiya
Yumi
Y
Kurihara
Atsushi
A
Kazui
Miho
M
Farid
Nagy A
NA
Ikeda
Toshihiko
T
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D000077144:Clopidogrel; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D000068799:Prasugrel Hydrochloride; D011725:Pyridines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C510685:R-138727; D013876:Thiophenes; C446540:thienopyridine; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D010089:Oxidoreductases, N-Demethylating; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine