Doxorubicin encapsulated in sterically stabilized liposomes exhibits renaland biliary clearance properties that are independent of valspodar (PSC 833) under conditions that significantly inhibit nonencapsulated drug excretion

Coadministration of anticancer drugs and multidrug resistance modulators di rected against P-glycoprotein overexpressed in tumors also results in nonsp ecific blockade of this drug efflux pump in excretory tissues such as the l iver and kidneys. These interactions often result in impaired renal and bil iary clearance for anticancer agents such as doxorubicin (DOX). In the pres ent investigation, we characterized the excretory processes associated with liposomal DOX administration to elucidate how liposome encapsulation may b ypass adverse pharmacokinetic interactions between DOX and (3'-keto-Bmt(1)) -(Val(2))-cyclosporin (Valspodar), Renal and biliary clearance properties o f liposome-encapsulated DOX were compared with those for nonencapsulated DO X in the presence and absence of Valspodar using an instrumented rat model with implanted jugular vein and bile duct catheters for continuous sampling . Two types of liposomal DOX formulations were used, a drug-permeable egg p hosphatidyl choline/cholesterol system and a sterically stabilized polyethy lene glycol/1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol system t o establish the relative roles of liposome-encapsulated and released drug o n the pharmacokinetic and excretion alterations induced by Valspodar, DOX a nd its primary metabolites were quantitated using high-performance liquid c hromatography. When Valspodar was coadministered with nonencapsulated DOX, 3.5- and 37.5-fold reductions in renal clearance (CLr) and biliary clearanc e (CLb), respectively, were observed, which resulted in increased plasma DO X concentrations and total exposure. However, Valspodar-induced alterations in CLr and CLb were less profound with egg phosphatidyl choline/cholestero l DOX (1.7- and 2.0-fold reductions, respectively) and negligible with the long-circulating polyethylene glycol-containing liposomal formulation. Thes e results indicate that liposomes may circumvent Valspodar-induced DOX phar macokinetic changes by reducing the rate of drug excretion in liver and kid ney tissue to a level that is within the renal and biliary excretion capaci ty in the presence of P-glycoprotein blockade.