Pharmacokinetics and preventive effects of targeted catalase derivatives on hydrogen peroxide-induced injury in perfused rat liver.
OBJECTIVE
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 111In-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.
Yabe
Yoshiyuki
Y
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Kobayashi
Naoki
N
Nishikawa
Makiya
M
Mihara
Kiyoshi
K
Yamashita
Fumiyoshi
F
Takakura
Yoshinobu
Y
Hashida
Mitsuru
M
D000818:Animals; D002374:Catalase / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002417:Cattle; D016503:Drug Delivery Systems / Q000379:methods*; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D002374:Catalase