title: Clopidogrel inhibits CYP2C19-dependent hydroxylation of omeprazole related to CYP2C19 genetic polymorphisms.
abstract: This study explores the impact of clopidogrel on the pharmacokinetics of omeprazole related to CYP2C19 genetic polymorphisms. Twelve healthy volunteers (6 CYP2C19*1/*1, 5 CYP2C19*2/*2, and 1 CYP2C19*2/*3) are enrolled in a 2-phase randomized crossover trial. In each phase, the volunteers are administered a single oral dose of omeprazole 40 mg after pretreatment of either placebo or clopidogrel (300 mg on the first day and then 75 mg once daily for 3 consecutive days). Plasma concentrations of omeprazole and its metabolites are quantified by high-performance liquid chromatography with UV detection. After clopidogrel treatment, the AUC(0-infinity) of omeprazole increases by 30.02% +/- 18.03% (P = .004) and that of 5-hydroxyomeprazole decreases by 24.30% +/- 11.66% (P = .032) in CYP2C19*1/*1. The AUC(0-infinity) ratios of omeprazole to 5-hydroxyomeprazole increase by 74.98% +/- 35.48% (P = .001) and those of omeprazole to omeprazole sulfone do not change significantly (P = .832) in CYP2C19*1/*1. No significant alteration is observed in CYP2C19*2/*2 or *3. Clopidogrel inhibits CYP2C19-dependent hydroxylation of omeprazole in CYP2C19*1/*1 and has no impact on CYP3A4-catalyzed sulfoxidation of omeprazole.
authors.affiliation: Pharmacogenetics Research Institute, Institute of Clinical Pharmacology Central South University, Changsha, Hunan, PR China.
authors.forename: B L
authors.initials: BL
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: J H
authors.initials: JH
authors.lastname: Tu
authors.forename: Y L
authors.initials: YL
authors.lastname: Li
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Fan
authors.forename: Z R
authors.initials: ZR
authors.lastname: Tan
authors.forename: D L
authors.initials: DL
authors.lastname: Hu
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.forename: L S
authors.initials: LS
authors.lastname: Wang
authors.forename: D S
authors.initials: DS
authors.lastname: Ouyang
authors.forename: H H
authors.initials: HH
authors.lastname: Zhou
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000097:blood; D000897:Anti-Ulcer Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008297:Male; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D013056:Spectrophotometry, Ultraviolet; D013454:Sulfoxides / Q000378:metabolism; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D010975:Platelet Aggregation Inhibitors; D013454:Sulfoxides; C049963:5-hydroxymethylomeprazole; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D013988:Ticlopidine