MANIPULATION OF RENAL DISPOSITION OF HUMAN RECOMBINANT SUPEROXIDE-DISMUTASE BY CHEMICAL MODIFICATION

The renal disposition characteristics of superoxide dismutase (SOD) an d its derivatives, including macromolecular conjugates with polyethyle ne glycol and carboxymethyl-dextran, a cationized derivative, and glyc osylated derivatives with galactose and mannose, were studied in the i solated perfused rat kidney. Renal disposition processes, such as glom erular filtration, tubular reabsorption, and uptake from the capillary side, were quantitatively determined by single-pass indicator dilutio n experiments under filtering and nonfiltering kidney conditions. Nati ve SOD had a high glomerular filtration rate (40% of that of inulin) a nd was effectively reabsorbed in the tubules, while no significant upt ake 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 tissu e, not only from the luminal side but also from the capillary side, ba sed upon electrostatic interaction. Galactosylated and mannosylated SO D showed reduced tubular reabsorption and increased exposure of the lu minal surface to the enzyme. In addition, a small but significant upta ke of mannosylated SOD from the capillary side was observed. This upta ke was dose-dependent and completely inhibited by mannan, suggesting t hat mannose receptor-mediated endocytosis existed in the capillary sid e of the kidney. Thus, we can manipulate the renal disposition profile s of son by changing its physicochemical or biological properties thro ugh chemical modification.