1994年1月
CONTROL OF THE DISPOSITION PROFILES OF PROTEINS IN THE KIDNEY VIA CHEMICAL MODIFICATION
JOURNAL OF CONTROLLED RELEASE
- ,
- ,
- 巻
- 28
- 号
- 1-3
- 開始ページ
- 111
- 終了ページ
- 119
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/0168-3659(94)90158-9
- 出版者・発行元
- ELSEVIER SCIENCE BV
To construct the strategy to control the renal disposition profiles of protein drugs by chemical modification, studies were performed using the perfused rat kidney. Renal disposition processes, i.e., glomerular filtration, tubular reabsorption, and uptake from the vascular side, were quantitatively determined by single-pass indicator dilution experiments under filtering and non-filtering conditions. As the first step, the renal disposition characteristics of model protein drugs and macromolecules were evaluated. These studies clarified the relationship between physicochemical properties of macromolecules, such as molecular weight and electric charge, and their fate in the kidney in a quantitative manner. Based on these findings, an antioxidant enzyme, superoxide dismutase (SOD), selected as a therapeutic agent for various tissue injuries including renal failure mediated by reactive oxygen species, was chemically modified. Conjugation with macromolecules, polyethylene glycol and carboxymethyl dextran, decreased glomerular filtration of SOD. Cationization enabled the enzyme to distribute to the kidney from the capillary side and to be completely reabsorbed by the tubular epithelium after glomerular filtration based on electrostatic interaction. On the other hand, glycosylation with monosaccharides, galactose and mannose, significantly reduced its tubular reabsorption and enhanced its exposure to the luminal surface. Furthermore, the mannosylated derivative accumulated in the kidney from the vascular side via a mannose-recognition mechanism. Thus, the present study demonstrates that chemical modification is useful for the control of renal disposition characteristics of protein drugs.
- リンク情報
- ID情報
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- DOI : 10.1016/0168-3659(94)90158-9
- ISSN : 0168-3659
- Web of Science ID : WOS:A1994NA91200011