Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan.
OBJECTIVE
Bosentan, a dual endothelin ET(A/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 0.1-10mg/kg triggered a dose-dependent increase in biliary bilirubin excretion. In addition, doses (> or =10mg/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 (> or =10mg/kg), both under basal conditions and under intravenous taurocholate perfusion (2micromol/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.
Fouassier
Laura
L
Institut National de la Santé et de la Recherche Médicale Unité 402, Faculté de Médecine Saint Antoine, 27, rue Chaligny, 75571 cedex 12, France.
Kinnman
Nils
N
Lefèvre
Guillaume
G
Lasnier
Elisabeth
E
Rey
Colette
C
Poupon
Raoul
R
Elferink
Ronald P J Oude
RP
Housset
Chantal
C
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism; D001648:Bile Canaliculi / Q000187:drug effects / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism; D000077300:Bosentan; D002784:Cholesterol / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D008297:Male; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001647:Bile Acids and Salts; D001663:Bilirubin; D000077300:Bosentan; D002784:Cholesterol; D065128:Endothelin Receptor Antagonists; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010743:Phospholipids; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; C421109:multidrug resistance-associated protein 1