1995 Volume 10 Issue 4 Pages 566-575
This review describes our recent investigation on the pharmacokinetic analysis of liposome disposition, especially hepatic uptake of liposomes. We have examined the saturable uptake processes of liposomes by the liver and postulated a new kinetic model “Manpuku Model (Satiated Model)” which explains AUC-dependent saturation kinetics of liposome uptake by the liver. This model assumes that the hepatic uptake clearance (CLh) is described by the maximum hepatic uptake clearance (CLh, max), maximum hepatic uptake (Xmax) and the hepatic uptake (X) as CLh=CLh, max (1-X/Xmax). This model explains the saturation kinetics of hepatic uptake of liposomes well and can be applicable to characterize the saturation kinetics of other kinds of liposome uptake.
The mechanism of hepatic uptake of liposomes was investigated using isolated perfused liver and hepatic uptake of liposomes was shown to be enhanced by preincubation with serum. This opsonic activity was shown to be mediated via complement receptor mediated phagocytosis. The activation of complement system dependended on the size of liposomes. There are two kinds of uptake pathways, one via size dependent, complement receptor mediated pathway, the other is size independent, nonspecific pathway.
The intracellular disposition of liposomes was further examined using 125I-BSA as a degradable, aqueous phase marker in the isolated peritoneal macrophages. The intracellular degradation of liposomes was shown to be biphasic. The degradation process of liposomes was also examined in intact liver and biphasic pattern was confirmed. These results indicate heterogeneous intracellular disposition (both transport and degradation) of liposomes.
The rational strategies for the drug delivery system using liposomes will be developed based on both quantitative evaluation of liposome movement in blood circulation, hepatic uptake and intracellular disposition and clarification of the mechanisms of liposome uptake and intracellular disposition of liposomes.
