Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone
| Autor: | Teppei Shimizu, Hirotoshi Echizen, Noboru Tamura, Harumi Takahashi, Noriko Shioda, Hitoshi Tainaka, Toshio Yasumori, Suzuko Kubo, Yoshiaki Shimoyama, Teruki Sato |
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| Rok vydání: | 1999 |
| Předmět: |
Male
medicine.drug_class Pharmacology Benzbromarone chemistry.chemical_compound Cytochrome P-450 Enzyme System Pharmacokinetics Uricosuric Agent In vivo medicine Humans heterocyclic compounds Pharmacology (medical) cardiovascular diseases CYP2C9 Aged Cytochrome P-450 CYP2C9 Chemistry Anticoagulant Warfarin Anticoagulants Drug Synergism Stereoisomerism Middle Aged Uricosuric Agents Drug interaction Steroid 16-alpha-Hydroxylase Steroid Hydroxylases Microsomes Liver Female Aryl Hydrocarbon Hydroxylases medicine.drug |
| Zdroj: | Clinical Pharmacology & Therapeutics. 66:569-581 |
| ISSN: | 0009-9236 |
| DOI: | 10.1053/cp.1999.v66.103378001 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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