INHIBITION OF RHODAMINE-123 SECRETION BY CYCLOSPORINE-A AS A MODEL OFP-GLYCOPROTEIN MEDIATED TRANSPORT IN LIVER

The interaction between P-glycoprotein modulators and P-glycoprotein m ediated transport was investigated using rhodamine 123 in the isolated perfused rat liver of a mutant (TR(-)) rat strain. TR(-) rats, defici ent in the canalicular multispecific anion transport system, are unabl e to extrude organic anions (glucuronides) and therefore excrete solel y unconjugated rhodamine 123 via P-glycoprotein. Cyclosporin A, a modu lator of multidrug resistance in tumor cells, inhibited the biliary se a etion of rhodamine 123 dose dependently in a non-competitive manner. Both cyclosporin A and rhodamine inhibited photoaffinity labeling of immunoprecipitated P-glycoprotein with azidopine, indicating binding t o hepatic P-glycoprotein. Our results indicate that monitoring the bil iary rhodamine 123 secretion in the isolated perfused liver of TR(-) r ats offers a new system for testing modulators of P-glycoprotein like cyclosporin A.