SPECIES-DIFFERENCE IN THE DISPOSITION OF LIPOSOMES AMONG MICE, RATS, AND RABBITS - ALLOMETRIC RELATIONSHIP AND SPECIES-DEPENDENT HEPATIC-UPTAKE MECHANISM

Purpose. The species difference in the pharmacokinetics of liposomes w as investigated in mice, rats and rabbits. Methods. Liposomes were int ravenously injected at doses of 1, 10 and 100 (nmol/g body weight), an d the time courses of liposomes in blood, liver and spleen were measur ed. Pharmacokinetic parameters were regressed as a function of body we ight (BW) and dose of liposomes (D). The uptake mechanism of liposomes was also examined with the isolated perfused liver between rats and m ice. Results. Mean residence time increased with the increase of BW an d D of liposomes. This increase of mean residence time resulted from t he decreased total body clearance, which was principally explained by the species difference in the hepatic uptake clearance (CLh) of liposo mes. The parameter CLh was regressed well by a multiple regression as a function of BW and D. In this analysis, an exponent for BW was aroun d 0.5, which clearly indicates that smaller animals have higher uptake clearance per unit BW. Immunohistochemical analysis revealed that the re was no significant difference in the density of Kupffer cells among these species. This suggest that the species difference in CLh result ed not from the density of Kupffer cells but from the uptake ability o f Kupffer cells amoung species. In the isolated perfused liver, the he patic uptake of liposomes was mainly explained by opsonin dependent up take in rats, while opsonin independent uptake in mice. Conclusions. T hese quantitative and qualitative information on the species differenc e of liposome disposition will provide an useful information for const ructing a drug delivery system using liposomes.