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 (greater than or equal to 10 mg/kg) caused a sustained increase in canalicular bile salt-independent bile flow, combined with significant increases in the concentration and output or glutathione and of bicarbonate in bile. In rats receiving bosentan (greater than or equal to 10 mg/kg), both under basal conditions and under intravenous taurocholate perfusion (2mumol/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. (C) 2002 European Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.