Advance Access publication February 10, 2010 Contribution of High Basolateral Bile Salt Efflux to the Lack of Hepatotoxicity in Rat in Response to Drugs Inducing Cholestasis

Intrahepatic bile acid accumulation due to inhibition of the bile salt export pump (BSEP) has been proposed as a mechanism for drug-induced cholestasis. Many cholestatic drugs do not initiate hepatotoxicity in rats, although they inhibit rat Bsep and cause elevated serum bile acid concentration. In this study, we examined changes in the taurocholate (TC) transport in response to cholestatic drug treatments in human and rat sandwich-cultured hepatocytes. Our experimental setup allows studying the baso-lateral and canalicular efflux simultaneously, thus comparing drug-induced changes in the vectorial efflux of TC. We found that TC elimination highly differs in human and rat hepatocytes. In human hepatocytes, an equal fraction of TCuptake was eliminated by basolateral (34.8%) and canalicular (34.4%) transporters and remained in the cells (30.5%), while in the case of rats, the basolateral transport was dominant (71.7%) and intracellular T