Improvement of therapeutic effect of human recombinant superoxide dismutase on ischemic acute renal failure in the rat via cationization and conjugation with polyethylene glycol.
Therapeutic effect of superoxide dismutase (SOD) and three derivatives: a conjugate with polyethylene glycol (SOD-PEG2), a cationized derivative (cSOD), and a mannosylated derivative (Man-SOD), on acute renal failure induced by ischemia/reperfusion was studied in rats. SOD and derivatives were administered intravenously to the rat after nephrectomy of the right kidney and before and after 60 min occlusion of the left renal artery. At 48 hr after reperfusion, the renal function was evaluated by determining the urinary excretion rate of 14C-inulin injected intravenously. No therapeutic effect on the impaired renal function was shown in the case of low dose SOD (2600 unit/kg) treatment. In contrast, administration of cSOD which was shown to be taken up by the isolated perfused kidney from its capillary side and SOD-PEG2 which maintained high plasma concentration exhibited significant therapeutic effect, as did SOD at ten-fold higher dose (26,000 unit/kg). On the other hand, renal damage was promoted by Man-SOD. Thus, the present study demonstrated that chemical modification may improve the therapeutic effect of SOD on the ischemic acute renal failure and increased SOD concentration in the renal vascular space is an important factor for the improved effect.
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
K
K
Mihara
Y
Y
Oka
K
K
Sawai
Y
Y
Takakura
M
M
Hashida
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D002412:Cations; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000378:metabolism; D016503:Drug Delivery Systems; D006801:Humans; D007275:Injections, Intravenous; D007444:Inulin / Q000652:urine; D007677:Kidney Function Tests; D008297:Male; D008358:Mannose / Q000737:chemistry / Q000378:metabolism; D009392:Nephrectomy; D011092:Polyethylene Glycols / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy*; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*
D002412:Cations; D004337:Drug Carriers; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D007444:Inulin; D013482:Superoxide Dismutase; D008358:Mannose