Effect of the endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin

Citation
C. Weber et al., Effect of the endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin, J CLIN PHAR, 39(8), 1999, pp. 847-854
Citations number
19
Categorie Soggetti
Pharmacology,"Pharmacology & Toxicology
Journal title
JOURNAL OF CLINICAL PHARMACOLOGY
ISSN journal
00912700 → ACNP
Volume
39
Issue
8
Year of publication
1999
Pages
847 - 854
Database
ISI
SICI code
0091-2700(199908)39:8<847:EOTEAB>2.0.ZU;2-W
Abstract
To investigate the effects of bosentan (Ro 47-0203), an endothelin receptor antagonist on the pharmacokinetics and pharmacodynamics of warfarin, a dou ble-blind, placebo-controlled randomized, two-way crossover study was perfo rmed in 12 healthy male volunteers. AN subjects received a single oral dose of 26 mg racemic warfarin twice, once in the morning of the 6th day of tre atment with 500 mg bosentan twice daily for 10 days and once at the same ti me point during treatment with placebo twice daily for 10 days. Both treatm ents were separated by a 2- to 3-week washout period. Blood samples were co llected at intervals up to 120 hours following the warfarin dose for th mea surement of prothrombin time and factor VII activity and for determination of plasma concentrations of R- and S-warfarin. Bosentan treatment led to a statistically significant reduction of the maximal prothrombin time (PTmax) and the AUC(0-120h) of PT and factor VII activity compared to placebo, on average, by 23% to 38%. This reduction could be explained by an increase in the elimination of the pharmacologically more active S-enantiomer whose me an AUC(0-infinity) was reduced by 29%. The mean AUC(0-infinity) of R-warfar in wets also decreased by 38%. C-max and t(max) of both enantiomers did not change. Close monitoring in patients receiving warfarin is recommended at initiation or discontinuation of treatment with bosentan. Journal of Clinic al Pharmacology, 1999;39:847-854 (C) 1999 the American College of Clinical Pharmacology.