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

Abstract

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.

• Authors: H Takahashi, T Sato, Y Shimoyama, N Shioda, T Shimizu, S Kubo, N Tamura, H Tainaka, T Yasumori, H Echizen
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 66 Issue 6 Pg. 569-81 (Dec 1999) ISSN: 0009-9236 [Print] United States
• PMID: 10613612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Aged
• Anticoagulants (blood, pharmacokinetics, urine)
• Aryl Hydrocarbon Hydroxylases
• Benzbromarone (blood, pharmacokinetics, 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, pharmacokinetics, urine)
• Warfarin (blood, pharmacokinetics, urine)