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Clin Pharmacol Ther. 2014 Oct;96(4):498-507. doi: 10.1038/clpt.2014.141. Epub 2014 Jun 27.

Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions.

Author information

1
1] Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland [2] HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
2
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
3
Center for Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.

Abstract

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-∞)) 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.

PMID:
24971633
DOI:
10.1038/clpt.2014.141
[Indexed for MEDLINE]

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