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

To investigate the effects of bosentan (Ro 47-0203), an endothelin receptor antagonist on the pharmacokinetics and pharmacodynamics of warfarin, a double-blind, placebo-controlled randomized, two-way crossover study was performed 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 treatment with 500 mg bosentan twice daily for 10 days and once at the same time point during treatment with placebo twice daily for 10 days. Both treatments were separated by a 2- to 3-week washout period. Blood samples were collected at intervals up to 120 hours following the warfarin dose for th measurement 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 mean AUC(0-infinity) was reduced by 29%. The mean AUC(0-infinity) of R-warfarin 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 Clinical Pharmacology, 1999;39:847-854 (C) 1999 the American College of Clinical Pharmacology.