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Vol. 59, Issue 3, 627-635, March 2001
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Non-Clinical
Development 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
Ki value, 1.3 µM), 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
Ki value of 0.23 µM. A comparable
inhibition was observed for both compounds in canalicular plasma
membrane vesicles prepared from Mrp2-deficient (TR
Drug Safety, Basel, Switzerland
) 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.
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