Stereoselective Interaction of Omeprazole with Warfarin in Healthy Men

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Abstract
The effect of concomitant treatment with omeprazole (20 mg/day) on the plasma concentration and anticoagulation effect of warfarin was studied in 21 young healthy men. An initial three weeks'' treatment with warfarin alone was administered to determine the doses required for the subjects'' vitamin K-dependent coagulation factors to fall within 10-20% of the normal range, as determined by the Trombotest. Omeprazole and placebo were then administered concomitantly with warfarin for 2 weeks each in a double-blind, randomized, crossover fashion. Plasma concentrations of (R)- and (S)-warfarin, and Trombotest values were measured daily on weekdays throughout the crossover period. Omeprazole had no apparent effect on the mean (S)-warfarin plasma concentration (379 ng/ml with, versus 387 ng/ml without, omeprazole), but caused a slightly (12%) although statistically significant increase in the mean (R)-warfarin concentration from 490 to 548 ng/ml (95% confidence interval for difference of means: 28-88). The Trombotest values exhibited large inter- and intrasubject variability during both omeprazole and placebo tratment; however, there was a small, although statistically significant decrease in the mean value from 21.1% without to 18.7% with omeprazole treatment (95% CI for difference of means: -4.6- -0.1). Those subjects with Trombotest values nearest the therapeutic range (5-15%) exhibited less change during omeprazole treatment, and no changes occurred that required a change in warfarin dosing. The interaction of omeprazole with warfarin was attributed to a stereoselective inhibition of the hepatic metabolism of the less potent (R)-warfarin enantiomer. The small effect of omeprazole on the anticoagulation activity of warfarin is not likely to be of clinical importance.