title: Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions.
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.
authors: 1] Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland [2] HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors: A
authors: A
authors: Tornio
authors: Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
authors: A M
authors: AM
authors: Filppula
authors: Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
authors: O
authors: O
authors: Kailari
authors: Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
authors: M
authors: M
authors: Neuvonen
authors: Center for Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors: T H
authors: TH
authors: Nyrönen
authors: 1] Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland [2] HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors: T
authors: T
authors: Tapaninen
authors: 1] Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland [2] HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors: P J
authors: PJ
authors: Neuvonen
authors: 1] Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland [2] HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors: M
authors: M
authors: Niemi
authors: 1] Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland [2] HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors: J T
authors: JT
authors: Backman
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002219:Carbamates / Q000493:pharmacokinetics; D020134:Catalytic Domain; D000077144:Clopidogrel; D003198:Computer Simulation; D065727:Cytochrome P-450 CYP2C8 / Q000737:chemistry; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D004347:Drug Interactions; D005260:Female; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics; D008297:Male; D050217:Metabolic Detoxication, Phase II; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000493:pharmacokinetics; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors
chemical_list: D002219:Carbamates; D020719:Glucuronides; D007004:Hypoglycemic Agents; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; C072379:repaglinide; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine