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

Clin Pharmacol Ther. 1999 Dec;66(6):569-81. doi: 10.1053/cp.1999.v66.103378001.


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 (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 formation clearance for 7-hydroxylation (CLf), the unbound oral clearance (CL(oral,u)), and the oral clearance (CL(oral)) 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, CL(oral),u, and CL(oral) 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 micromol/L) for (S)-warfarin 7-hydroxylation mediated by CYP2C9. The average changes in the in vivo CLf, CL(oral),u, and CL(oral)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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anticoagulants / blood
  • Anticoagulants / pharmacokinetics*
  • Anticoagulants / urine
  • Aryl Hydrocarbon Hydroxylases*
  • Benzbromarone / blood
  • Benzbromarone / pharmacokinetics*
  • Benzbromarone / urine
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Synergism
  • Female
  • Humans
  • Male
  • Microsomes, Liver / enzymology
  • Middle Aged
  • Stereoisomerism
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / metabolism
  • Uricosuric Agents / blood
  • Uricosuric Agents / pharmacokinetics*
  • Uricosuric Agents / urine
  • Warfarin / blood
  • Warfarin / pharmacokinetics*
  • Warfarin / urine


  • Anticoagulants
  • Uricosuric Agents
  • Benzbromarone
  • Warfarin
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Steroid 16-alpha-Hydroxylase