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ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2',7'-DICHLOROFLUORESCEIN IN Abcg2 (Bcrp1) AND Abcc2 (Mrp2) KNOCKOUT MICE

University of North Carolina, School of Pharmacy, Chapel Hill, North Carolina (K.N., X.T., M.J.Z.-G., K.L.R.B.); and Eli Lilly and Company, Department of Drug Disposition, Indianapolis, Indiana (N.J.P., T.J.R.)

This study characterized the hepatobiliary disposition of 5 (and 6)-carboxy-2',7'-dichlorofluorescein (CDF), a model Abcc2/Mrp2 (canalicular) and Abcc3/Mrp3 (basolateral) substrate, in perfused livers from male C57BL/6 wild-type, Abcg2–/–, and Abcc2–/– mice. After single-pass liver perfusion with 1 µM CDF diacetate for 30 min and an additional 30-min perfusion with CDF-free buffer, cumulative biliary excretion of CDF in Abcg2–/– mice was significantly higher than in wild-type mice (65 ± 6 and 47 ± 15% of dose, respectively, p < 0.05), whereas CDF recovery in bile of Abcc2–/– mice was negligible. Cumulative recovery of CDF in perfusate was significantly higher in Abcc2–/– (90 ± 8% of dose) relative to wild-type (35 ± 11% of dose) mice. Compartmental pharmacokinetic analysis revealed that the rate constant for CDF biliary excretion was significantly increased in Abcg2–/– (0.061 ± 0.005 min^–1) compared with wild-type (0.039 ± 0.011 min^–1) mice. The rate constant governing the basolateral excretion of CDF was 4-fold higher in Abcc2–/– (0.12 ± 0.02 min^–1) relative to wild-type (0.030 ± 0.011 min^–1) mice but was not altered in Abcg2–/– (0.031 ± 0.004 min^–1) mice. Hepatic Abcc3 protein levels, determined by immunoblot analysis, were 60% higher in Abcc2–/– mice than in wild-type mice. In contrast, neither Abcc3 protein levels nor Abcc2 mRNA levels were altered in Abcg2–/– relative to wild-type mice. These data in knockout mouse models demonstrate that loss of expression and function of one canalicular transport protein may change the route and/or extent of excretion into bile or perfusate because of alterations in the function of other basolateral or canalicular transport proteins.

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