Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone

Objective: To clarify the mechanism(s) for the interaction between warfarin and benzbromarone, a uricosuric agent, and to predict changes in the in vi vo pharmacokinetics of (S)-warfarin from in vitro data, Methods: Warfarin enantiomers and benzbromarone in serum, 7-hydroxywarfarin in urine, and serum unbound fractions of warfarin enantiomers were measure d in patients with heart disease given warfarin with (n = 13) or without (n = 18) oral benzbromarone (50 mg/d), In vitro inhibition constants (K-i) of benzbromarone for (S)-warfarin 7-hydroxylation were determined with use of human CYP2C9 and liver microsomes, The magnitude of changes in the formati on clearance for 7-hydroxylation (CLf), the unbound oral clearance (CLoral, u), and the oral clearance (CLoral) for (S)-warfarin were predicted by equa tions incorporating the in vitro K-i, the theoretical maximum unbound hepat ic benzbromarone concentration, and the fractions of warfarin eliminated th rough metabolism and of CYP2C9-mediated metabolic reaction susceptible to i nhibition by benzbromarone, Results: The patients given warfarin with benzbromarone required a 36% less (P < .01) warfarin dose than those given warfarin alone (2.5 versus 3.9 mg /d) to attain similar international normalized ratios (2.1 and 2.2, respect ively), and the former had 65%, 53%, and 54% lower (P < .05 or P < .01) CLf , CLoral,u, and CLoral for (S)-warfarin than the latter, respectively, In c ontrast, no significant differences were observed for (R)-warfarin kinetics between the groups. Benzbromarone was found to be a potent competitive inh ibitor (K-i < 0.01 mu mol/L) for (S)-warfarin 7-hydroxylation mediated by C YP2C9. The average changes in the in vive CLf, CLoral,u, and CLoral values for (S)-warfarin induced by benzbromarone were largely predictable by the p roposed equations, Conclusion: Benxbromarone would intensify anticoagulant response of warfari n through an enantioselective inhibition of CYP2C9-mediated metabolism of p harmacologically more potent (S)-warfarin, The magnitude of changes in the in vive warfarin kinetics may be predicted by in vitro data.