ANTIVIRAL EFFICACY, INTRACELLULAR UPTAKE AND PHARMACOKINETICS OF FREEAND LIPOSOME-ENCAPSULATED 2',3'-DIDEOXYINOSINE

Objective: To evaluate the effect of liposome encapsulation on the in vitro antiviral efficacy, intracellular uptake and in vivo pharmacokin etics of 2',3'-dideoxyinosine (ddl). Methods: The accumulation of free and liposome-encapsulated ddl was determined in murine monocyte-macro phage RAW 264.7 cells and human premonocytoid U937 cells. The antivira l efficacy was evaluated in U937 cells infected with HIVIIIB. Tissue d istribution and pharmacokinetics of free and liposomal ddl were determ ined in female Sprague-Dawley rats following the administration of a s ingle intravenous bolus dose (3 mg ddl/kg). Results: The entrapment of ddl in liposomes results in a lower drug accumulation in both U937 an d RAW 264.7 cells. A lower antiviral efficacy against HIVIIIB replicat ion in U937 cells was observed on encapsulation of ddl in liposomes. I mproved pharmacokinetics were observed on entrapment of ddl in liposom es. Higher drug levels were found in plasma for the liposomal formulat ion. The systemic clearance of the liposomal drug was 120 times lower than that of free drug. Liposome encapsulation of ddl greatly enhanced the drug accumulation in organs of the reticuloendothelial system. Co nclusion: The encapsulation of ddl in liposomes modified the tissue di stribution and plasma pharmacokinetics of the antiviral agent resultin g in a marked improvement of drug biodisponibility. The antiviral effi cacy of liposomal ddl was lower than that of free drug in HIVIIIB-infe cted U937 cells.