The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: A potential mechanism for hepatic adverse reactions

Background: During clinical trials bosentan, the first orally active endoth elin receptor antagonist, caused asymptomatic transaminase elevations in so me patients. In this study we investigated whether inhibition of the hepato canalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) coul d account for bosentan-induced liver injury. Methods: We reanalyzed the safety database of the bosentan trials for chole static liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediat ed taurocholate transport in vitro. Results: Bosentan caused dose-dependent and reversible liver injury in 2% t o 18% of patients and caused a significant increase of serum bile salt leve ls (P <.01). Concomitant administration of glyburide (INN, glibenclamide) e nhanced the cholestatic potency of bosentan. Similar effects were seen in r ats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibite d by bosentan (inhibition constant, -12 <mu>mol/L) and metabolites (inhibit ion constant, -8.5 mu mol/L for metabolite Ro 47-8634). Conclusions: These results indicate that bosentan-induced liver injury is m ediated, at least in part, by inhibition of Bsep/BSEP-causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell dama ge. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury.