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Received for publication October 21, 2005.
Revised January 18, 2006.
Accepted for publication January 19, 2006.
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 was not excreted into bile of Abcc2-/- mice. Cumulative recovery of CDF in perfusate was significantly higher in Abcc2-/- (90 ± 8% of dose) relative to wild-type mice (35 ± 11% of dose). Compartmental pharmacokinetic analysis revealed that the rate constant for CDF biliary excretion was significantly increased in Abcg2-/- (0.061 ± 0.005 min-1) compared to wild-type mice (0.039 ± 0.011 min-1). 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 mice (0.030 ± 0.011 min-1), but was not altered in Abcg2-/- mice (0.031 ± 0.004 min-1). 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 due to alterations in the function of other basolateral or canalicular transport proteins.
Key words:
ABC transporters, hepatobiliary disposition, MRP, pharmacokinetic modeling
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