THE EFFECT OF DOSE ON THE DISTRIBUTION OF ADRIAMYCIN ENCAPSULATED IN POLYETHYLENEGLYCOL-COATED LIPOSOMES

The distributiort of adriamycin (ADR) at a clinically relevant low dose of 2.5 mg/kg was compared to the distribution at a high dose of 7.5 mg/kg (dose often employed in distribution studies). ADR solution (ADRsol), plain liposomal ADR (PLADR) and polyethyleneglycol (PEG)-coated liposomal ADR (PEG-LADR) were injected into the tail vein of Wistar rats. The retention in serum was PEG-LADR > PLADR > ADRsol at both doses. In the high-dose study, ADR concentration in the liver and spleen at 4 h after administrations of PLADR and PEG-LADR were higher than that with ADRsol. On the other hand, in the low-dose study, reticuloendothelial system (RES) uptake of ADR was reduced by liposome encapsulation (liposomalization). Reduced ADR concentrations in the heart due to liposomalization were found only at the low doses. These results indicate that the difference in doses led to different distributions and that there is an optimal dose at which liposomes exhibit their objective distribution. A comparison of the ADR concentration in the spleen to that in the liver indicated RES saturation by increasing doses and the optimal dose being lower than the dose that saturates RES. Thus, distribution of liposome-entrapped ADR must be investigated at doses as close to the clinical dose as possible.