1994年
CONTROL OF IN-VIVO FATE OF ALBUMIN DERIVATIVES UTILIZING COMBINED CHEMICAL MODIFICATION
JOURNAL OF DRUG TARGETING
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- 巻
- 2
- 号
- 2
- 開始ページ
- 157
- 終了ページ
- 165
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.3109/10611869409015905
- 出版者・発行元
- HARWOOD ACAD PUBL GMBH
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 (less-than-or-equal-to 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 (CL(liver)) were decreased at administered doses higher than 1mg/kg, e.g. 10, 20, and 100mg/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., CL(liver) 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 CL(liver) 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 ManBSA at 24h 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.
- リンク情報
- ID情報
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- DOI : 10.3109/10611869409015905
- ISSN : 1061-186X
- PubMed ID : 8069594
- Web of Science ID : WOS:A1994NP98500009