Hepatobiliary disposition of the metabolically stable opioid peptide [D-Pen2, D-Pen5]-enkephalin (DPDPE): pharmacokinetic consequences of the interplay between multiple transport systems.

[D-Pen2,D-Pen5]-Enkephalin (DPDPE) is excreted extensively into the bile. Although DPDPE is transported by P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (Mrp2) has been identified as an important mechanism for DPDPE transport across the canalicular membrane of the hepatocyte. The present studies determined the relative impact of Mrp2 and P-gp on the hepatobiliary disposition of [3H]DPDPE in isolated perfused rat livers (IPLs). Perfusate clearance of [3H]DPDPE was not different between livers from control and Mrp2-deficient (TR-) rats. Biliary excretion of [3H]DPDPE in IPLs from Wistar control rats was rapid and extensive. However, when [3H]DPDPE was administered to livers from TR- rats, the rate and extent of excretion decreased significantly. Surprisingly, in the presence of the P-gp inhibitor GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide], biliary excretion of [3H]DPDPE was not inhibited in control livers. In contrast, administration of GF120918 to TR- livers further reduced the maximal excretion rate and decreased net biliary excretion of [3H]DPDPE by 87%. GF120918 administration caused an unexpected increase in perfusate clearance in both control and TR- rat livers. At distribution equilibrium, [3H]DPDPE liver/perfusate partitioning was higher in GF120918-treated livers. Results of pharmacokinetic modeling were consistent with the hypothesis that GF120918 inhibited a [3H]DPDPE basolateral excretion mechanism. Mrp2 is the primary mechanism for [3H]DPDPE biliary excretion, and P-gp facilitates excretion of [3H]DPDPE only in the absence of functional Mrp2. [3H]DPDPE is a substrate for a basolateral efflux mechanism that is sensitive to inhibition by GF120918. These data emphasize the importance of using appropriate model systems and comprehensive pharmacokinetic modeling in elucidating the complex interplay between multiple transport systems.