Comparison of mechanism-based inhibition of human cytochrome P450 2C19 by ticlopidine, clopidogrel, and prasugrel

Abstract

1. Mechanism-based inhibition of CYP2C19 in human liver microsomes by the thienopyridine antiplatelet agents clopidogrel, prasugrel and their thiolactone metabolites was investigated by determining the time- and concentration-dependent inhibition of the activity of S-mephenytoin 4′-hydroxylase as typical CYP2C19 activity and compared with ticlopidine and its metabolite.

2. Clopidogrel was shown to be a mechanism-based inhibitor of CYP2C19 with the inactivation kinetic parameters, k_inact and K_I, equal to 0.0557 min⁻¹ and 14.3 μM, respectively, as well as ticlopidine (0.0739 min⁻¹ and 3.32 μM, respectively). The thiolactone metabolite of ticlopidine and clopidogrel inhibited CYP2C19 only in a concentration-dependent manner. In contrast, neither prasugrel nor its thiolactone metabolite inhibited CYP2C19 at concentrations up to 100 μM.

3. The oxidation of the thiophene moiety of clopidogrel to form their respective thiolactones was found to be the critical reaction that produces the chemically reactive metabolites which cause the mechanism-based inhibition of CYP2C19.

4. Estimation of in vivo drug–drug interaction using in vitro parameters predicted clinically observed data. For clopidogrel, there was no increase in the area under the curve (AUC) at its clinical dose level as predicted by the in vitro parameters, and for ticlopidine the prediction agreed with the clinically observed AUC increase.

5. In conclusion, clopidogrel is potent mechanism-based inhibitors of CYP2C19 as well as ticlopidine, whereas prasugrel did not inactivate CYP2C19. Administration of prasugrel would not cause a clinically relevant interaction with CYP2C19.

Keywords::

• Prasugrel
• ticlopidine
• clopidogrel
• thienopyridine
• mechanism-based inhibition
• CYP2C19.

Acknowledgements

The authors wish to thank Dr Mary Pat Knadler of Eli Lilly & Co. for her helpful comments on the manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.