Inhibition of bile acid transport by cyclosporine A in rat liver plasma membrane vesicles.

In selectively isolated basolateral (bILPM) and canalicular (cLPM) rat liver plasma membrane vesicles, the in vitro effect of cyclosporine A (CsA) on specific hepatic membrane transport processes was examined. CsA (0.1-200 microM) caused a concentration-dependent inhibition of initial rates of Na(+)-dependent taurocholate uptake in bILPM and cLPM vesicles and Na(+)-independent taurocholate efflux from cLPM vesicles. In contrast, CsA had no effect on Na(+)-dependent L-alanine uptake in bILPM and in cLPM vesicles. In addition, electroneutral pH gradient-driven Na+ uptake in bILPM vesicles was unaffected by CsA treatment. CsA-induced inhibition of taurocholate transport in bILPM and cLPM vesicles was competitive in nature. A hydroxylated (OL-17) and a N-demethylated (OL-21) metabolite of CsA had no effect on taurocholate transport in either membrane vesicle population. These findings suggest that the mechanism of CsA-induced cholestasis is, in part, the result of selective inhibition of bile acid transport by the parent compound at both domains of the hepatocyte plasma membrane.