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

: Tornio A, Filppula AM, Kailari O, Neuvonen M, Nyronen TH, Tapaninen T, Neuvonen PJ, Niemi M, Backman JT

Publisher: NATURE PUBLISHING GROUP

: 2014

: Clinical Pharmacology and Therapeutics

: CLINICAL PHARMACOLOGY & THERAPEUTICS

: CLIN PHARMACOL THER

: 96

: 4

: 498

: 507

: 10

: 0009-9236

DOI: https://doi.org/10.1038/clpt.2014.141

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 (AUC(0-infinity)) 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-beta-D-glucuronide as a potent time-dependent inhibitor of CYP2C8. A physiologically based pharmacokinetic model indicated that inactivation of CYP2C8 by clopidogrel acyl-beta-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment. Computational modeling resulted in docking of clopidogrel acyl-beta-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-beta-D-glucuronide and imply that glucuronide metabolites should be considered potential inhibitors of CYP enzymes.