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MODULATION OF HEPATIC CANALICULAR OR BASOLATERAL TRANSPORT PROTEINS ALTERS HEPATOBILIARY DISPOSITION OF A MODEL ORGANIC ANION IN THE ISOLATED PERFUSED RAT LIVER

School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (P.C., B.M.J., G.M.P., K.L.R.B.); and Qualyst, Inc., Research Triangle Park, North Carolina (P.Z.)

This study examined the impact of hepatic transport protein modulation on the hepatobiliary disposition of a nonmetabolized probe substrate, 5- (and 6)-carboxy-2',7'dichlorofluorescein (CDF) in rat isolated perfused livers (IPLs). In vivo treatment with modulators (100 and 200 mg/kg/day clofibric acid, 80 mg/kg/day phenobarbital, and 25 mg/kg/day dexamethasone) was used to alter the expression of hepatic transport proteins [organic anion transporting polypeptide 1a1, multidrug resistance-associated protein (Mrp) 3, and Mrp2] governing the disposition of CDF. The basolateral and biliary excretion of CDF was measured in single-pass IPLs from control and treated rats. Modulators increased the percentage of CDF eliminated into perfusate of IPLs from treated rats (20-35%) compared with controls (10%); CDF biliary excretion was decreased in the treated groups. These observations are consistent with modulator-associated increases in the first-order rate constant governing CDF excretion from the hepatocytes into perfusate (k_perfusate) or decreases in the first-order rate constant governing CDF excretion into bile (k_bile). Pharmacokinetic modeling of the data and subsequent simulations revealed that the routes of CDF excretion were most sensitive to changes in k_perfusate. In contrast, hepatic accumulation of CDF was most sensitive to k_bile. The differential sensitivity of CDF excretory routes and hepatic accumulation to these rate constants is a function of intrahepatic distribution kinetics, which must be taken into consideration in assessing the potential impact of altered hepatobiliary transport processes.

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