2002年12月
Pharmacokinetics and preventive effects of targeted catalase derivatives on hydrogen peroxide-induced injury in perfused rat liver
PHARMACEUTICAL RESEARCH
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- 巻
- 19
- 号
- 12
- 開始ページ
- 1815
- 終了ページ
- 1821
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1023/A:1021485222920
- 出版者・発行元
- KLUWER ACADEMIC/PLENUM PUBL
Purpose. To investigate the pharmacokinetics and preventive effects of liver- targeted catalase (CAT) derivatives on hepatic injury caused by reactive oxygen species.
Methods. The hepatic uptake of In-111-CAT, galactosylated (Gal-), mannosylated (Man-) and succinylated (Suc-) CAT was investigated in isolated perfused rat livers in a single- pass constant infusion mode. Then, pharmacokinetic parameters were obtained by fitting equations derived from a one- organ pharmacokinetic model to the outflow profile. Their effects in preventing hydrogen peroxide- induced injury were determined by lactate dehydrogenase (LDH) release from the perfused liver.
Results. The extraction of CAT derivatives by the liver was dose-dependent, and increased by the chemical modifications described. After being bound to the cell surface, chemically modified CAT derivatives were internalized by the liver faster than CAT. Preperfusion of a CAT derivative significantly reduced LDH release by hydrogen peroxide at least for 30 min, and Man- CAT and Suc- CAT effectively inhibited this release.
Conclusions. Internalized CAT derivatives are also effective in degrading hydrogen peroxide and targeted delivery of CAT to liver nonparenchymal cells by mannosylation or succinylation is a useful method for the prevention of hepatic injury caused by reactive oxygen species.
Methods. The hepatic uptake of In-111-CAT, galactosylated (Gal-), mannosylated (Man-) and succinylated (Suc-) CAT was investigated in isolated perfused rat livers in a single- pass constant infusion mode. Then, pharmacokinetic parameters were obtained by fitting equations derived from a one- organ pharmacokinetic model to the outflow profile. Their effects in preventing hydrogen peroxide- induced injury were determined by lactate dehydrogenase (LDH) release from the perfused liver.
Results. The extraction of CAT derivatives by the liver was dose-dependent, and increased by the chemical modifications described. After being bound to the cell surface, chemically modified CAT derivatives were internalized by the liver faster than CAT. Preperfusion of a CAT derivative significantly reduced LDH release by hydrogen peroxide at least for 30 min, and Man- CAT and Suc- CAT effectively inhibited this release.
Conclusions. Internalized CAT derivatives are also effective in degrading hydrogen peroxide and targeted delivery of CAT to liver nonparenchymal cells by mannosylation or succinylation is a useful method for the prevention of hepatic injury caused by reactive oxygen species.
- リンク情報
- ID情報
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- DOI : 10.1023/A:1021485222920
- ISSN : 0724-8741
- PubMed ID : 12523659
- Web of Science ID : WOS:000179746600007