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Received for publication January 11, 2005.
Revised May 18, 2005.
Accepted for publication May 19, 2005.
This study examined the impact of hepatic transport protein modulation on the hepatobiliary disposition of a non-metabolized 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 (Oatp)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 to 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 (kperfusate) or decreases in the first-order rate constant governing CDF excretion into bile (kbile). Pharmacokinetic modeling of the data and subsequent simulations revealed that the routes of CDF excretion were most sensitive to changes in kperfusate. In contrast, hepatic accumulation of CDF was most sensitive to kbile. 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.
Key words:
ABC transporters, hepatic transport, hepatic uptake, hepatobiliary disposition, hepatobiliary transport, MRP, organic anion transport, pharmacokinetic modeling, pharmacokinetics, transporters
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