title: Dose-dependent interaction between gemfibrozil and repaglinide in humans: strong inhibition of CYP2C8 with subtherapeutic gemfibrozil doses.
abstract: Gemfibrozil 1-O-β-glucuronide inactivates CYP2C8 irreversibly. We investigated the effect of gemfibrozil dose on CYP2C8 activity in humans using repaglinide as a probe drug. In a randomized, five-phase crossover study, 10 healthy volunteers ingested 0.25 mg of repaglinide 1 h after different doses of gemfibrozil or placebo. Concentrations of plasma repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. A single gemfibrozil dose of 30, 100, 300, and 900 mg increased the area under the concentration-time curve of repaglinide 1.8-, 4.5-, 6.7-, and 8.3-fold (P < 0.001), and its peak concentration 1.4-, 1.7-, 2.1-, and 2.4-fold (P < 0.05), compared with placebo, respectively. Gemfibrozil pharmacokinetics was characterized by a slightly more than dose-proportional increase in the area under the curve of gemfibrozil and its glucuronide. The gemfibrozil-repaglinide interaction could be mainly explained by gemfibrozil 1-O-β-glucuronide concentration-dependent, mechanism-based inhibition of CYP2C8, with a minor contribution by competitive inhibition of organic anion-transporting polypeptide 1B1 at the highest gemfibrozil dose. The findings are consistent with ∼50% inhibition of CYP2C8 already with a single 30-mg dose of gemfibrozil and >95% inhibition with 900 mg. In clinical drug-drug interaction studies, a single 900-mg dose of gemfibrozil can be used to achieve nearly complete inactivation of CYP2C8.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki, and HUSLAB Laboratory Services, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Honkalammi
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D015248:Gemfibrozil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002219:Carbamates; D027361:Organic Anion Transporters; D010880:Piperidines; C072379:repaglinide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D015248:Gemfibrozil