Effects of dose and vesicle size on the pharmacokinetics of liposomes.

Abstract

The blood concentration and urinary excretion after intravenous injection of liposomes containing 3H-inulin at three dose levels were examined in rats. A pharmacokinetic model for the dose dependency is postulated based on the results. The effects of vesicle size were also examined and the biological disposition was simulated. Factors affecting the liposomal disposition are discussed. Dose dependency of the disposition was observed at three dose levels (1.8, 14.9 and 70.3 .mu.mol total lipids/rat) of liposomes having a mean diameter of 0.22 .mu.m. The results suggest that existence of saturable processes in the uptake of liposomes by the reticuloendothelial system (RES) and leakage of inulin from liposomes, and a first-order rate process in the release of inulin from the cell after degradation of liposomes taken up by the RES. However, simulation of the data obtained after high-dose administration was unsuccessful with this model, the blood clearance of liposomes being faster than calculated. It is suggested that first-order processes may operate in parallel with the saturable processes of uptake and leakage. The effects of the size of liposomes (mean diameter: 0.15, 0.22 and 0.43 .mu.m) on the disposition were also examined. The patterns of the blood levels and urinary excretion of small liposomes and large liposomes were very similar to those of the high-dose and low-dose experiments, respectively, in spite of the very similar dose levels of total lipids administered. Simulation suggested that the dose expressed in terms of the number of vesicles was suitable for evaluation of the liposomal disposition. The results indicate that the size and number of liposomes are important variables affecting the disposition of liposomes and they should be controlled strictly in liposomes for in vivo use.