A1 Refereed original research article in a scientific journal
Glucuronidation Converts Clopidogrel to a Strong Time-Dependent Inhibitor of CYP2C8: A Phase II Metabolite as a Perpetrator of Drug-Drug Interactions
Authors: Tornio A, Filppula AM, Kailari O, Neuvonen M, Nyronen TH, Tapaninen T, Neuvonen PJ, Niemi M, Backman JT
Publisher: NATURE PUBLISHING GROUP
Publication year: 2014
Journal: Clinical Pharmacology and Therapeutics
Journal name in source: CLINICAL PHARMACOLOGY & THERAPEUTICS
Journal acronym: CLIN PHARMACOL THER
Volume: 96
Issue: 4
First page : 498
Last page: 507
Number of pages: 10
ISSN: 0009-9236
DOI: https://doi.org/10.1038/clpt.2014.141
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-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.
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.
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