HEPATIC-UPTAKE AND TISSUE DISTRIBUTION OF LIPOSOMES - INFLUENCE OF VESICLE SIZE

The size-dependent disposition of liposomes in rats was studied. Lipos omes consisting of phosphatidylcholine, cholesterol, dicetylphospate a nd alpha-tocopherol in a molar ratio of 4:4:1:1, containing a trace of [C-14]-labeled cholesterol as a marker of the lipid phase, were prepa red and sized by extruding through polycarbonate membrane. [H-3]-inuli n was used as a marker of the aqueous phase. In situ liver perfusion i n rats showed that hepatic extraction of liposomes was significant for multilamellar vesicles (MLVs) larger than 0.4 mu m (0.40, 0.82 and 1. 31 mu m) and small unilamellar vesicles (SW), but negligible for 0.25 mu m MLV. Pharmacokinetic analysis after intravenous (i.v.) injection showed that the area under the plasma elimination curve (AUC) was sign ificantly higher, but the volume of distribution (Vd) and the eliminat ion rate constant (ke) were significantly lower for the 0.25 mu m than for the 1.31 mu m liposomes. Comparing the distribution of 1.36 and 0 .25 mu m MLVs after i.v. injection, the 1.31 mu m MLV showed a signifi cantly higher concentration in liver and spleen, but lower concentrati on in plasma and kidney, than the 0.26 mu m in terms of dose percent. These results suggest that size is one of the important factors affect ing the fate of liposmes in vivo. There must be a minimun size for eff ective uptake of liposomes by the reticuloendothelial system. If below the minimum effective uptake size, the MLV should remain in higher co ncentration in circulation.