Species difference in the disposition of liposomes among mice, rats, and rabbits: allometric relationship and species dependent hepatic uptake mechanism.
OBJECTIVE
The species difference in the pharmacokinetics of liposomes was investigated in mice, rats and rabbits.


METHODS
Liposomes were intravenously injected at doses of 1, 10 and 100 (nmol/g body weight), and the time courses of liposomes in blood, liver and spleen were measured. Pharmacokinetic parameters were regressed as a function of body weight (BW) and dose of liposomes (D). The uptake mechanism of liposomes was also examined with the isolated perfused liver between rats and mice.


RESULTS
Mean residence time increased with the increase of BW and D of liposomes. This increase of mean residence time resulted from the decreased total body clearance, which was principally explained by the species difference in the hepatic uptake clearance (CLh) of liposomes. 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 around 0.5, which clearly indicates that smaller animals have higher uptake clearance per unit BW. Immunohistochemical analysis revealed that there was no significant difference in the density of Kupffer cells among these species. This suggest that the species difference in CLh resulted not from the density of Kupffer cells but from the uptake ability of Kupffer cells among species. In the isolated perfused liver, the hepatic uptake of liposomes was mainly explained by opsonin dependent uptake in rats, while opsonin independent uptake in mice.


CONCLUSIONS
These quantitative and qualitative information on the species difference of liposome disposition will provide an useful information for constructing a drug delivery system using liposomes.
Harashima
H
H
Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
Komatsu
S
S
Kojima
S
S
Yanagi
C
C
Morioka
Y
Y
Naito
M
M
Kiwada
H
H
D000818:Animals; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000187:drug effects; D008081:Liposomes / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009895:Opsonin Proteins / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013154:Spleen / Q000378:metabolism
D008081:Liposomes; D009895:Opsonin Proteins