The effect of troglitazone biliary excretion on metabolite distribution and cholestasis in transporter-deficient rats

We investigated whether lack of the canalicular multispecific organic anion transporter in transport-deficient (TR-) rats would result in plasma and u rinary accumulation of troglitazone or its major metabolites and whether an y accumulation would be associated with increased levels of bilirubin or bi le acids. Administration of a single oral dose of troglitazone (200 mg/kg) to TR- rats resulted in 2- and 50-fold increases in plasma levels and 30- a nd 500-fold increases in urinary amounts of troglitazone sulfate and trogli tazone glucuronide, respectively, compared with normal rats. No changes wer e found in the plasma concentrations and urinary amounts of troglitazone or troglitazone-quinone. Accumulation of troglitazone metabolites in plasma w as accompanied by a 2-fold increase in the serum level of conjugated biliru bin in TR-rats, whereas no changes were observed in normal animals. Bile ac ids were detected in the urine of both TR- and normal rats, with an average 3-fold greater level found in the urine of TR-animals. Biliary metabolic p rofiles revealed a delay in the secretion of troglitazone sulfate and trogl itazone glucuronide in TR-rats over the first 2- and 4-h periods, respectiv ely. These results demonstrate the role of multidrug resistant associated p rotein-2 in biliary secretion of troglitazone glucuronide and troglitazone sulfate and suggest the presence of compensatory mechanisms responsible for transport of troglitazone metabolites and bilirubin-glucuronide at the bas olateral and canalicular sites of hepatocytes.