Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate

Troglitazone is a thiazolidinedione insulin sensitizer drug for the treatme nt of type 2 non-insulin-dependent diabetes mellitus (NIDDM). Based on an i ncreasing number of reports on troglitazone-associated liver toxicity, the cholestatic potential of troglitazone and its major metabolite troglitazone sulfate has been investigated. In isolated perfused rat livers troglitazon e (10 muM) reduced the bile flow by 25% (female) to 50% (male) within 60 mi n. After single intravenous administrations of troglitazone to rats of both genders, rapid and dose-dependent increases in the plasma bile acid concen trations were observed, with male rats being more sensitive than female rat s. In male rat liver tissue fivefold higher troglitazone sulfate levels wer e measured as compared to female rat liver tissue. This difference was due to the formation rate of troglitazone sulfate, which was four times faster in cytosolic fractions of male rat liver as compared to female rat liver (C lint = 132 and 35 mul min(-1) mg(-1), respectively). Troglitazone sulfate s trongly inhibited the ATP-dependent taurocholate transport mediated by the canalicular bile salt export pump (Bsep) in isolated canalicular rat liver plasma membrane preparations of both genders (IC50 value of 0.4-0.6 muM), w hile troglitazone was 10 times less potent (IC50 values of 3.9 muM). This h igh Bsep inhibition potential and the efficient formation and accumulation of troglitazone sulfate in liver tissue, suggested that troglitazone sulfat e was mainly responsible for the interaction with the hepatobiliary export of bile acids at the level of the canalicular Bsep in rats. Such an interac tion might lead potentially also in man to a troglitazone-induced intrahepa tic cholestasis, potentially contributing to the formation of troglitazone- induced liver injuries. (C) 2001 Elsevier Science Ireland Ltd. All rights r eserved.