The Role of Cytochrome P2C19 in R-warfarin Pharmacokinetics and its Interaction With Omeprazole

Abstract

Previous studies reported omeprazole to be an inhibitor of cytochrome P450 (CYP) 2C19 and suggested the pharmacokinetic interaction of omeprazole with R-warfarin. The aim of this study was to compare possible effects of omeprazole on the stereoselective pharmacokinetics and pharmacodynamics of warfarin between CYP2C19 genotypes. Seventeen subjects, of whom 10 were homozygous extensive metabolizers (hmEMs) and seven were poor metabolizers (PMs) for CYP2C19, were enrolled in this randomized crossover study, and they ingested 20 mg omeprazole or placebo once daily for 11 days. On day 7, they administered a single dose of 10 mg racemic warfarin. The plasma concentrations of warfarin enantiomers and prothrombin time expressed as international normalized ratio were monitored up to 120 hours. During the placebo phase, area under the plasma concentration-time curve (AUC) and elimination half-life (t1/2) of R-warfarin in PMs was significantly greater than those in hmEMs (AUC[0-infinity], 42,938/34,613 ng h/mL [PM/hmEM], P = 0.004; t1/2, 48.8/40.8 hours [PM/hmEM], P = 0.013). Omeprazole treatment significantly increased the AUC(0-infinity) (41,387 ng h/mL, P = 0.004) and t1/2 (46.4 hours, P = 0.017) of R-warfarin in hmEMs to levels comparable to those in the PMs. There were no differences in S-warfarin pharmacokinetics between the CYP2C19 genotypes (AUC[0-infinity], 15,851/16,968 ng*h/mL [PM/hmEM]; t1/2, 22.7/25.4 h [PM/hmEM]), or between the two treatment phases (AUC[0-infinity], 14,756/18,166 ng h/mL [PM/hmEM]; t1/2, 27.0/25.4 hours [PM/hmEM] in the omeprazole phase) as well as anticoagulant effects. These results indicate that CYP2C19 activity was one of determinants on the R-warfarin disposition because the pharmacokinetics of warfarin enantiomers were different between the CYP2C19 genotypes and the omeprazole affected the R-warfarin pharmacokinetics of CYP2C19 in only hmEMs. However, the phamacodynamic effect of the interaction of warfarin with omeprazole would be of minor clinical significance.