Competitive Mechanisms in the Hepatic Uptake of Liposomes In Vivo

Abstract

We have postulated a “satiated model” to explain the saturable hepatic uptake clearance of liposomes. This model assumes that the hepatic uptake clearance (CL_h) decreases in proportion to the hepatic uptake amount. We have examined the competitive mechanisms in the hepatic uptake of liposomes using three kinds of liposomes composed of egg phosphatidylcholine (EPC) or hydrogenated EPC with cholesterol (Chol), and dicetylphosphate (DCP). Male Wistar rats were administered marker liposomes (2 μmol lipid/kg) consisting of multi-lamellar vesicles (MLV) composed of HEPC/Chol/DCP (HEPC-MLV^*) alone (control) or with empty liposomes (200 μmol lipid/kg). The marker liposomes were also administered after 4 h of EPC-MLV injection. The CL_h of HEPC-MLV^* was remarkably decreased by 97% with empty, small unilamellar vesicles (SUV) composed of HEPC/Chol/DCP (HEPC-SUV). This result indicated that HEPC-SUV inhibited CL_h of HEPC-MLV^* by depleting serum opsonins. HEPC-SUV was suggested to inhibit the hepatic uptake of HEPC-MLV^* according to the Michaelis-Menten model. On the other hand, competition by MLV composed of EPC/Chol/DCP (EPC-MLV) in the hepatic uptake of HEPC-MLV^* was low, and there was no difference in the hepatic uptake amount of HEPC-MLV^* with or without EPC-MLV. Pre-administration of empty EPC-MLV inhibited the CL_h of HEPC-MLV^* remarkably. These results indicate that empty EPC-MLV did not consume serum opsonins and were taken up via a different uptake pathway than that of HEPC-MLV^*. EPC-MLV was suggested to inhibit the uptake of HEPC-MLV^* after being taken up by the liver via some negative feedback mechanisms, which is explained by the satiated model.

We clarified that there were at least two kinds of competition mechanisms in the hepatic uptake of liposomes.