Comparison of Human Cytochrome P450 Inhibition by the Thienopyridines Prasugrel, Clopidogrel, and Ticlopidine

Abstract

  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 IC₅₀ values of 0.0517±0.0323 μM and 0.0182±0.0069 μM, respectively, and inhibited CYP2C19 with IC₅₀ values of 0.203±0.124 μM and 0.524±0.160 μM, respectively. Ticlopidine also inhibited CYP2D6 (IC₅₀ of 0.354±0.158 μM). 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.