1994年4月
PHARMACOKINETICS OF SUCCINYLATED PROTEINS AND DEXTRAN SULFATE IN MICE - IMPLICATIONS FOR HEPATIC TARGETING OF PROTEIN DRUGS BY DIRECT SUCCINYLATION VIA SCAVENGER RECEPTORS
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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- 巻
- 105
- 号
- 1
- 開始ページ
- 19
- 終了ページ
- 29
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/0378-5173(94)90231-3
- 出版者・発行元
- ELSEVIER SCIENCE BV
The disposition characteristics of three types of In-111-labeled succinylated proteins, succinylated superoxide dismutase (Suc-SOD; Mol. Wt 34000), bovine serum albumin (Suc-BSA; Mol. Wt 70000) and uricase (Suc-UC; Mol. Wt 130000) and [C-14]dextran sulfate (DS; Mol. Wt 8000) after intravenous injection were studied in mice. At a dose of 1 mg/ kg, [In-111]Suc-BSA and [In-111]Suc-UC were taken up by the liver to a great extent whereas [In-111]Suc-SOD was rapidly excreted into the urine without marked hepatic uptake. [In-111]Suc-BSA was preferentially localized in non-parenchymal cells of the liver. Rapid urinary excretion was observed for [C-14]DS, however, it accumulated in the liver. Hepatic uptake of [In-111]Suc-BSA and [C-14]DS was suppressed at a higher dose (100 mg/kg), suggesting a saturable uptake process. Pharmacokinetic analysis revealed that hepatic uptake clearances of [In-111]Suc-BSA, [In-111]Suc-UC and [C-14]DS were 15.8-, 7.2- and 10.4-fold higher than that of [In-111]Suc-SOD, respectively, at 1 mg/kg. Hepatic uptake of [In-111]Suc-BSA was significantly inhibited by simultaneous administration of excess amounts of other negatively charged macromolecules, such as maleylated BSA (Mal-BSA), heparin, DS and polyinosinic acid (poly[I]), typical ligands for scavenger receptors. On the other hand, native BSA, cationized BSA (Cat-BSA), galactosylated and mannosylated BSA (Gal- and Man-BSA), carboxymethyl dextran (CM-dex) and polycytidylic acid (poly[C]) were not effective inhibitors. Thus, this is the first report that protein drugs can be targeted to liver non-parenchymal cells by direct succinylation through scavenger receptors in vivo. In addition, the importance of molecular weight or total number of anionic charges per protein molecule was suggested.
- リンク情報
- ID情報
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- DOI : 10.1016/0378-5173(94)90231-3
- ISSN : 0378-5173
- J-Global ID : 200902179561504026
- Web of Science ID : WOS:A1994ND34400004