Glucuronidation Converts Clopidogrel to a Strong Time-Dependent Inhibitor of CYP2C8: A Phase II Metabolite as a Perpetrator of Drug-Drug Interactions

Cerivastatin and repaglinide are substrates of cytochrome P450 (CYP)2C8, CYP3A4, and organic anion–transporting polypeptide (OATP)1B1. A recent study revealed an increased risk of rhabdomyolysis in patients using cerivastatin with clopidogrel, warranting further studies on clopidogrel interactions. In healthy volunteers, repaglinide area under the concentration–time curve (AUC0–∞) was increased 5.1–fold by a 300–mg loading dose of clopidogrel and 3.9–fold by continued administration of 75 mg clopidogrel daily. In vitro, we identified clopidogrel acyl–β–D–glucuronide as a potent time–dependent inhibitor of CYP2C8. A physiologically based pharmacokinetic model indicated that inactivation of CYP2C8 by clopidogrel acyl–β–D–glucuronide leads to uninterrupted 60–85% inhibition of CYP2C8 during daily clopidogrel treatment. Computational modeling resulted in docking of clopidogrel acyl–β–D–glucuronide at the CYP2C8 active site with its thiophene moiety close to heme. The results indicate that clopidogrel is a strong CYP2C8 inhibitor via its acyl–β–D–glucuronide and imply that glucuronide metabolites should be considered potential inhibitors of CYP enzymes. Clinical Pharmacology & Therapeutics (2014); 96 4, 498–507. doi:10.1038/clpt.2014.141