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

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

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Aryl Hydrocarbon Hydroxylases / chemistry
  • Carbamates / pharmacokinetics
  • Catalytic Domain
  • Clopidogrel
  • Computer Simulation
  • Cytochrome P-450 CYP2C8 / chemistry
  • Cytochrome P-450 CYP3A / chemistry
  • Drug Interactions
  • Female
  • Glucuronides / metabolism*
  • Humans
  • Hypoglycemic Agents / pharmacokinetics
  • Male
  • Metabolic Detoxication, Phase II
  • Molecular Docking Simulation
  • Piperidines / pharmacokinetics
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / metabolism*
  • Platelet Aggregation Inhibitors / pharmacology
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / chemistry
  • Ticlopidine / metabolism
  • Ticlopidine / pharmacology
  • Time Factors

Substances

  • Carbamates
  • Glucuronides
  • Hypoglycemic Agents
  • Piperidines
  • Platelet Aggregation Inhibitors
  • repaglinide
  • Clopidogrel
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ticlopidine