Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan

Background/Aims: Bosentan, a dual endothelin ETA/B receptor antagonist, may cause dose-dependent reversible cholestatic liver injury. We herein tested whether bosentan or metabolites, both eliminated in bile, induce alterations in bile secretion. Methods: Bile flow and output of bile constituents were monitored in pentobarbital-anesthetized rats with biliary fistulas. Normal and TR− rats with a genetic defect in mrp2, received bosentan intravenous injections. Results: Bosentan bolus intravenous injections of 0.1–10 mg/kg triggered a dose-dependent increase in biliary bilirubin excretion. In addition, doses (≥10 mg/kg) caused a sustained increase in canalicular bile salt-independent bile flow, combined with significant increases in the concentration and output of glutathione and of bicarbonate in bile. In rats receiving bosentan (≥10 mg/kg), both under basal conditions and under intravenous taurocholate perfusion (2μmol/min/kg), phospholipid and cholesterol secretions were profoundly inhibited and uncoupled from bile salt secretion. In TR− rats, the choleretic effect of bosentan was reduced to non-significant levels. The stimulation of bilirubin secretion and the uncoupling of phospholipid from bile salt secretion were absent, whereas that of cholesterol was maintained. Conclusions: Bosentan alters canalicular bile formation in major part via mrp2-mediated mechanisms. Intermittent uncoupling of lipid from bile salt secretion may contribute to bosentan hepatic adverse reaction.