Cholestatic potential of troglitazone as a possible factor contributing totroglitazone-induced hepatotoxicity: In vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat

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 has been investigated. Rapid and dose -dependent increases in the plasma bile acid concentrations were observed i n rats after a single intravenous administration of troglitazone. A radiola beled taurocholic acid tracer accumulated in liver tissue, indicating an in terference with the hepatobiliary export of bile acids. In isolated canalic ular rat liver plasma membrane preparations, troglitazone competitively inh ibited the ATP-dependent taurocholate transport (apparent K-i value, 1.3 mu M), 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 muM. A comp arable inhibition was observed for both compounds in canalicular plasma mem brane 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 metabol ite might represent a rate-limiting step in the overall elimination process of troglitazone. This accumulation in combination with the high Bsep inhib ition potential suggested that mainly troglitazone sulfate was responsible for the interaction with the hepatobiliary export of bile acids at the leve l of the canalicular Bsep in rats. Such an interaction might lead to a trog litazone-induced intrahepatic cholestasis in humans as well, contributing t o the formation of a troglitazone-induced liver toxicity.