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The hepatobiliary disposition of thyroxine (T4) was evaluated in Groningen Yellow transport deficient (TR−) rats lacking functional multidrug resistance–associated protein 2 (Mrp2; Abcc2). Male Wistar and TR− rats were dosed orally (4 days) with phenobarbital (PB; 100 mg/kg) or DMP 904 (200 mg/kg), after which T4 homeostasis and hepatic cytochromes P450, UDP-glucuronosyltransferase, xenobiotic transporters, and T4 glucuronidation were determined. Serum concentrations of T4 were approximately 50% higher in control TR− rats than Wistars. PB and DMP 904 increased hepatic levels of P450s and T4-glucuronidation (T4-G), and these changes were associated with decreased serum T4 levels in both strains. In Wistar but not TR− rats, DMP 904 increased thyroid stimulating hormone levels twofold. Hepatobiliary clearance of T4 was determined after intravenous infusion of [125I]T4 to rats dosed with PB and DMP 904 (4 days). PB and DMP 904 increased plasma clearance and hepatic uptake of [125I]T4 equivalents in Wistar but not TR− rats. Total biliary clearance (Clbile) was approximately 0.85 and 0.2 ml/h in Wistar and TR− rats, respectively, with virtually no T4-G excreted in bile in TR− rats. Biliary clearance of unconjugated T4 was also lower in control TR− rats than in Wistars, although DMP 904 increased its biliary clearance in both strains. These results suggest that Mrp2 is likely to be responsible for biliary excretion of T4-G and contributes in part to excretion of T4. Decreased biliary clearance of T4 and metabolites in TR− rats mitigated but did not prevent drug-induced changes in serum T4, suggesting that other factors contribute to changes in T4 homeostasis in these rats. [ABSTRACT FROM AUTHOR]