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 vivo 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 measured in patients with heart disease given warfarin with (n = 13) or without (n = 18) oral benzbromarone (50 mg/d). In vitro inhibition constants (Ki) of benzbromarone for (S)‐warfarin 7‐hydroxylation were determined with use of human CYP2C9 and liver microsomes. The magnitude of changes in the formation clearance for 7‐hydroxylation (CLf), the unbound oral clearance (CLoral,u), and the oral clearance (CLoral) for (S)‐warfarin were predicted by equations incorporating the in vitro Ki, the theoretical maximum unbound hepatic benzbromarone concentration, and the fractions of warfarin eliminated through metabolism and of CYP2C9‐mediated metabolic reaction susceptible to inhibition 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, respectively), 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 contrast, no significant differences were observed for (R)‐warfarin kinetics between the groups. Benzbromarone was found to be a potent competitive inhibitor (Ki < 0.01 μmol/L) for (S)‐warfarin 7‐hydroxylation mediated by CYP2C9. The average changes in the in vivo CLf, CLoral,u, and CLoral values for (S)‐warfarin induced by benzbromarone were largely predictable by the proposed equations. Conclusion Benzbromarone would intensify anticoagulant response of warfarin through an enantioselective inhibition of CYP2C9‐mediated metabolism of pharmacologically more potent (S)‐warfarin. The magnitude of changes in the in vivo warfarin kinetics may be predicted by in vitro data. Clinical Pharmacology & Therapeutics (1999) 66, 569–581; doi: 10.1053/cp.1999.v66.103378001