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Vol. 29, Issue 12, 1561-1566, December 2001
Departments of Drug Safety Evaluation Department (V.E.K., D.A.),
Pharmacokinetics, Dynamics, and Metabolism (E. K., J.B.), and
Laboratory Animal Resources (K.R., G.P.), Pfizer Global Research and
Development, Ann Arbor, Michigan; Graduate Center for Toxicology
(M.V.), University of Kentucky, Lexington, Kentucky; and Pharmaceutical
Research Institute (M.W.S.), Bristol-Myers Squibb, Wallingford,
Connecticut
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.
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