title: Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat.
abstract: Troglitazone is a thiazolidinedione insulin sensitizer drug for the treatment of type 2 non-insulin-dependent diabetes mellitus (NIDDM). Based on an increasing number of reports on troglitazone-associated liver toxicity, the cholestatic potential of troglitazone has been investigated. Rapid and dose-dependent increases in the plasma bile acid concentrations were observed in rats after a single intravenous administration of troglitazone. A radiolabeled taurocholic acid tracer accumulated in liver tissue, indicating an interference with the hepatobiliary export of bile acids. In isolated canalicular rat liver plasma membrane preparations, troglitazone competitively inhibited the ATP-dependent taurocholate transport (apparent K(i) value, 1.3 microM), mediated by the canalicular bile salt export pump (Bsep). Troglitazone sulfate, the main troglitazone metabolite eliminated into bile, also showed competitive Bsep inhibition with an apparent K(i) value of 0.23 microM. A comparable inhibition was observed for both compounds in canalicular plasma membrane vesicles prepared from Mrp2-deficient (TR(-)) rats, suggesting a direct (cis-) inhibition of Bsep by troglitazone and troglitazone sulfate. A high accumulation potential was observed for troglitazone sulfate in rat liver tissue, indicating that the hepatobiliary export of this conjugated metabolite might represent a rate-limiting step in the overall elimination process of troglitazone. This accumulation in combination with the high Bsep inhibition potential suggested that mainly troglitazone sulfate was responsible for the interaction with the hepatobiliary export of bile acids at the level of the canalicular Bsep in rats. Such an interaction might lead to a troglitazone-induced intrahepatic cholestasis in humans as well, contributing to the formation of a troglitazone-induced liver toxicity.
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Non-Clinical Development-Drug Safety, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Funk
authors.forename: C
authors.initials: C
authors.lastname: Ponelle
authors.forename: G
authors.initials: G
authors.lastname: Scheuermann
authors.forename: M
authors.initials: M
authors.lastname: Pantze
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001648:Bile Canaliculi / Q000187:drug effects* / Q000378:metabolism; D001667:Binding, Competitive; D001692:Biological Transport; D002756:Cholagogues and Choleretics / Q000493:pharmacokinetics; D002839:Chromans / Q000378:metabolism / Q000633:toxicity*; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid / Q000493:pharmacokinetics; D013844:Thiazoles / Q000378:metabolism / Q000633:toxicity*; D045162:Thiazolidinediones; D000077288:Troglitazone
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490548:Abcb11 protein, rat; D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D013656:Taurocholic Acid; D000077288:Troglitazone