ENCAPSULATION OF FOSCARNET IN LIPOSOMES MODIFIES DRUG INTRACELLULAR ACCUMULATION, IN-VITRO ANTI-HIV-1 ACTIVITY, TISSUE DISTRIBUTION AND PHARMACOKINETICS
N. Dusserre et al., ENCAPSULATION OF FOSCARNET IN LIPOSOMES MODIFIES DRUG INTRACELLULAR ACCUMULATION, IN-VITRO ANTI-HIV-1 ACTIVITY, TISSUE DISTRIBUTION AND PHARMACOKINETICS, AIDS, 9(8), 1995, pp. 833-841
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.