Effect of omeprazole on the hydroxylation of warfarin enantiomers in human: in-vitro studies with liver microsomes and cDNA-expressed cytochrome P450 isozymes

Abstract

Clinically observed warfarin-omeprazole interaction has been found to be associated with the inhibition of R-warfarin hydroxylation by omeprazole. The present study was conducted in human liver microsomes and cDNA-expressed cytochrome P450s to assess the inhibitory potential of omeprazole on the hydroxylation of warfarin enantiomers, and to identify the cytochrome P450 isozymes involved in the inhibition of hydroxylation of warfarin enantiomers by omeprazole, and to evaluate the extent to which the in vitro data is predictive of the actual pharmacokinetic interaction between warfarin and omeprazole observed in vivo. Omeprazole inhibited the formation of R-6-, R-7- and S-7-hydroxywarfarin with the Ki values of 40, 22 and 116 microM, respectively. Its inhibitory effect was selective towards R-warfarin. Further study conducted in cDNA-expressed cytochrome P450s (CYPs) demonstrates that the inhibition of the in-vitro biotransformation of warfarin enantiomers by omeprazole is attributed to its inhibitory effect on the activities of CYP1A2, CYP3A4, CYP2C9 and CYP2C19. The extent of the in vivo warfarin-omeprazole interaction was underestimated as based on the Ki values obtained from the in-vitro inhibition study, suggesting an underestimation of the effective concentration of the inhibitor at the site of interaction or some other mechanisms involved in the drug interaction between warfarin and omeprazole.