Demonstration of the receptor-mediated hepatic uptake of dextran in mice.
To establish a rationale of designing a drug targeting system using dextran conjugation, the disposition behaviour of dextran itself was investigated in mice. At a high dose (100 mg kg-1), [14C]dextran was retained in the blood circulation for a considerably long period. However, [14C]dextran rapidly disappeared from the plasma and accumulated in the liver (up to 60% of dose in 1 h) after a dose of 1 mg kg-1. Cellular localization of [14C]dextran in the liver following intravenous administration was examined and the contribution of parenchymal cells was demonstrated as well as the case of galactosylated bovine serum albumin (Gal-BSA). Pharmacokinetic analysis based on a physiological model including Michaelis-Menten type uptake mechanisms revealed that the Michaelis constant Km,l of [14C]dextran was 100 times greater than that of Gal-BSA. Coadministration of Gal-BSA delayed the hepatic uptake of [14C]dextran and the simulation based on the physiological model suggested that [14C]dextran was taken up by the same mechanism as Gal-BSA. These results suggested that dextran conjugation of a drug might lead to its undesirable accumulation in the liver at a low dose and an appropriate modification of dextran, such as carboxymethylation, would be required in such cases.
D000818:Animals; D003911:Dextrans / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D011971:Receptors, Immunologic / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000737:chemistry; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution
D003911:Dextrans; D011971:Receptors, Immunologic; C036109:dextran receptor; D012710:Serum Albumin, Bovine