RT Journal Article
SR Electronic
T1 The Effect of Troglitazone Biliary Excretion on Metabolite Distribution and Cholestasis in Transporter-Deficient Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1561
OP 1566
VO 29
IS 12
A1 Vsevolod E. Kostrubsky
A1 Mary Vore
A1 Erick Kindt
A1 James Burliegh
A1 Karen Rogers
A1 Gregory Peter
A1 Douglas Altrogge
A1 Michael W. Sinz
YR 2001
UL http://dmd.aspetjournals.org/content/29/12/1561.abstract
AB We investigated whether lack of the canalicular multispecific organic anion transporter in transport-deficient (TR−) rats would result in plasma and urinary accumulation of troglitazone or its major metabolites and whether any accumulation would be associated with increased levels of bilirubin or bile 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- and 500-fold increases in urinary amounts of troglitazone sulfate and troglitazone glucuronide, respectively, compared with normal rats. No changes were found in the plasma concentrations and urinary amounts of troglitazone or troglitazone-quinone. Accumulation of troglitazone metabolites in plasma was accompanied by a 2-fold increase in the serum level of conjugated bilirubin in TR− rats, whereas no changes were observed in normal animals. Bile acids 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 profiles revealed a delay in the secretion of troglitazone sulfate and troglitazone glucuronide in TR− rats over the first 2- and 4-h periods, respectively. These results demonstrate the role of multidrug resistant associated protein-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 basolateral and canalicular sites of hepatocytes. The American Society for Pharmacology and Experimental Therapeutics