TY - JOUR T1 - ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2′,7′-DICHLOROFLUORESCEIN IN <em>Abcg2</em> (Bcrp1) AND <em>Abcc2</em> (Mrp2) KNOCKOUT MICE JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 718 LP - 723 DO - 10.1124/dmd.105.007922 VL - 34 IS - 4 AU - Ken-ichi Nezasa AU - Xianbin Tian AU - Maciej J. Zamek-Gliszczynski AU - Nita J. Patel AU - Thomas J. Raub AU - Kim L. R. Brouwer Y1 - 2006/04/01 UR - http://dmd.aspetjournals.org/content/34/4/718.abstract N2 - 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 &lt; 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. The American Society for Pharmacology and Experimental Therapeutics ER -