ENCAPSULATION OF FOSCARNET IN LIPOSOMES MODIFIES DRUG INTRACELLULAR ACCUMULATION, IN-VITRO ANTI-HIV-1 ACTIVITY, TISSUE DISTRIBUTION AND PHARMACOKINETICS

Objective: To improve the in vitro anti-HIV-l activity, intracellular accumulation in macrophages and in vivo pharmacokinetics and tissue di stribution of foscarnet (trisodium phosphonoformate; PFA) by encapsula tion in liposomes. Methods: The accumulation of free and liposome-enca psulated PFA was determined in monocyte-macrophage RAW 264.7 cells and human premonocytoid U937 cells. The antiviral activity was evaluated in U937 cells infected with HIV-1(IIIB) Tissue distribution and pharma cokinetics of free and liposomal PFA were determined in female Sprague -Dawley rats following the administration of an intravenous bolus dose (10 mg PFA/kg). Results: The entrapment of PFA in liposomes resulted in a higher drug accumulation in both U937 and RAW 264.7 cells. A slig htly greater efficacy against HIV-1(IIIB) replication into U937 cells was observed upon encapsulation of PFA into liposomes. Improved pharma cokinetics was observed upon entrapment of PFA in liposomes. Much high er drug levels were found in plasma for the liposomal formulation. The systemic clearance of the liposomal drug was 77 times lower than that of free drug. The encapsulation of PFA in liposomes greatly enhanced the drug accumulation in organs of the reticuloendothelial system. Con clusion: The encapsulation of PFA in liposomes modified the tissue dis tribution and plasma pharmacokinetics of the antiviral agent, resultin g in a marked improvement of drug accumulation in organs involved in H IV immunopathogenesis and in a greater PFA bioavailability. The antivi ral activity of liposomal PFA was slightly greater than that of free d rug in HIV-1(IIIB)-infected U937 cells.