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
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.