Clinical studies on pharmacokinetic drug-drug interactions caused by clopidogrel : focus on CYP2C8-mediated drug metabolism

Clopidogrel, an adenosine diphosphate receptor subtype P2Y12 antagonist, attenuates platelet activation via its active cis-thiol metabolite formed in two steps predominantly by cytochrome P450 (CYP) 2C19 and CYP3A4. It is widely used in acute treatment and secondary prevention of atherothrombotic events. The acyl-β-D-glucuronide metabolite of clopidogrel acts as a time-dependent inhibitor of CYP2C8 in vitro, and consistently, clopidogrel markedly increases the exposure of the CYP2C8 and OATP1B1 substrate repaglinide in vivo. The primary aim of this work was to examine the potential of clopidogrel to cause drug-drug interactions (DDIs) with OATP1B1 and CYP2C8 substrates, while the secondary objective was to search for sensitive and selective CYP2C8 index substrates. This thesis consists of five prospective, clinical pharmacokinetic and pharmacodynamic DDI studies applying randomized, controlled, crossover design. In the first study, clopidogrel did not affect the pharmacokinetics of simvastatin, leading to the conclusion that clopidogrel is not a clinically relevant inhibitor of OATP1B1 or CYP3A4, which have paramount roles in the disposition of simvastatin. In the second and third studies, clopidogrel doubled the exposures of the CYP2C8 substrates pioglitazone and montelukast, respectively. In contrast, prasugrel did not significantly affect montelukast pharmacokinetics. The fourth study found clopidogrel to increase the exposure of the CYP2C8 substrate dasabuvir ~4–5-fold and observed ritonavir to markedly decrease the exposure of clopidogrel active metabolite and its antiplatelet effect. The results from the fourth study indicated that dasabuvir is a very sensitive and specific CYP2C8 substrate and that combining clopidogrel with dasabuvir or ritonavir with clopidogrel may risk patient safety. In the fifth study, clopidogrel significantly inhibited, and gemfibrozil almost completely prevented, the CYP2C8-mediated 3-hydroxylation of desloratadine. In conclusion, clopidogrel is a clinically relevant CYP2C8 inhibitor capable of causing potentially hazardous DDIs, and it can be employed as a selective index inhibitor of CYP2C8 in clinical DDI studies. Furthermore, dasabuvir could be applied as a CYP2C8 index substrate in subtherapeutic doses in clinical drug research. Moreover, the observations from this work corroborate the ability of ritonavir to disrupt CYP3A4-mediated bioactivation of prodrugs, including clopidogrel, which can compromise patient safety. Finally, these results highlight the ability of glucuronide metabolites to act as substrates and inhibitors of CYP enzymes, especially CYP2C8, and therefore they must be considered as potentially interacting compounds during drug development.