Clopidogrel inhibits CYP2C19-dependent hydroxylation of omeprazole related to CYP2C19 genetic polymorphisms.
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.
Chen
B L
BL
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology Central South University, Changsha, Hunan, PR China.
Chen
Y
Y
Tu
J H
JH
Li
Y L
YL
Zhang
W
W
Li
Q
Q
Fan
L
L
Tan
Z R
ZR
Hu
D L
DL
Wang
D
D
Wang
L S
LS
Ouyang
D S
DS
Zhou
H H
HH
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
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