Control of in vivo fate of albumin derivatives utilizing combined chemical modification.
Three types of bovine serum albumin (BSA) derivatives such as lactosylated BSA (LBSA), mannosylated BSA (Man-BSA), and cationized BSA (cBSA) were synthesized and their hepatic disposition characteristics in mice were evaluated by pharmacokinetic analysis. At lower doses (< or = 1 mg/kg), LBSA and Man-BSA were very rapidly eliminated from the blood circulation due to uptake by parenchymal and nonparenchymal cells of the liver, respectively, via receptor-mediated endocytosis (Nishikawa et al., 1992; Nishida et al., 1991a, b). These uptake processes were nonlinear and the apparent hepatic uptake clearances (CLliver) were decreased at administered doses higher than 1 mg/kg, e.g. 10, 20, and 100 mg/kg. The liver accumulation of cBSA was also nonlinear, but its binding and/or uptake capacity in the liver was larger than those of LBSA and Man-BSA; i.e., CLliver decreased at doses higher than 20 mg/kg. In the next step, we modified these BSA derivatives by attaching polyethylene glycol (PEG), a modifier known to reduce the hepatic uptake and increase plasma retention, to achieve precise control of the in vivo disposition characteristics of BSA derivatives. By conjugation with PEG having a molecular weight of 10 kDa, the CLliver values of LBSA, Man-BSA, and cBSA were decreasing to one-seventh, one-fortyfifth, and one-onehundredthirtieth, respectively. However, liver accumulation of PEG modified LBSA and Man-BSA at 24 h after i.v. injection was not significantly different from unmodified BSA derivatives. These results suggest that it is possible to control the hepatic uptake of protein drugs by a combination of introduction of charge or sugar moieties and PEG conjugation.
Fujita
T
T
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Nishikawa
M
M
Ohtsubo
Y
Y
Ohno
J
J
Takakura
Y
Y
Sezaki
H
H
Hashida
M
M
D000818:Animals; D002412:Cations / Q000737:chemistry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004705:Endocytosis / Q000187:drug effects; D005947:Glucose / Q000737:chemistry; D007205:Indium Radioisotopes; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011092:Polyethylene Glycols / Q000737:chemistry; D017457:Receptors, Albumin / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D002412:Cations; D007205:Indium Radioisotopes; D017457:Receptors, Albumin; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols; D005947:Glucose