Manipulation of renal disposition of human recombinant superoxide dismutase by chemical modification.
The renal disposition characteristics of superoxide dismutase (SOD) and its derivatives, including macromolecular conjugates with polyethylene glycol and carboxymethyl-dextran, a cationized derivative, and glycosylated derivatives with galactose and mannose, were studied in the isolated perfused rat kidney. Renal disposition processes, such as glomerular filtration, tubular reabsorption, and uptake from the capillary side, were quantitatively determined by single-pass indicator dilution experiments under filtering and nonfiltering kidney conditions. Native SOD had a high glomerular filtration rate (40% of that of inulin) and was effectively reabsorbed in the tubules, while no significant uptake was observed from capillary side. Macromolecular conjugates showed restricted glomerular filtration due to an increase in molecular size. Cationization of SOD greatly enhanced its association with the tissue, not only from the luminal side but also from the capillary side, based upon electrostatic interaction. Galactosylated and mannosylated SOD showed reduced tubular reabsorption and increased exposure of the luminal surface to the enzyme. In addition, a small but significant uptake of mannosylated SOD from the capillary side was observed. This uptake was dose-dependent and completely inhibited by mannan, suggesting that mannose receptor-mediated endocytosis existed in the capillary side of the kidney. Thus, we can manipulate the renal disposition profiles of SOD by changing its physicochemical or biological properties through chemical modification.
Mihara
K
K
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Sawai
K
K
Takakura
Y
Y
Hashida
M
M
D000818:Animals; D003911:Dextrans; D005690:Galactose; D005919:Glomerular Filtration Rate; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008297:Male; D008358:Mannose; D008970:Molecular Weight; D011092:Polyethylene Glycols; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000652:urine; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution
D003911:Dextrans; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C014392:carboxymethyl dextran; D013482:Superoxide Dismutase; D008358:Mannose; D005690:Galactose