Toxicological Approaches to Streptothricin Antibiotics. III. Biological Studies on Delayed Toxicity of Streptothricin Antibiotics in Rats

To delineate the time of onset and the mechanism of delayed toxic effects produced by streptothricin antibiotics in rats, the tissue antibiotic distribution, histopathologic features of the kidney, serum biochemical changes and antibiotic metabolites recovered in the urine after administration of a radiolabeled compound were investigated. Rats showed a pattern of tissue antibiotic distribution similar to that observed in the mouse. Microscopic examination of the kidney revealed lesions which became evident at 48 hr after the injection. Serum biochemical tests showed a rapid elevation of blood urea nitrogen and creatinine nitrogen levels from 48 hr post injection, with abnormalities in the cellulose acetate membrane electrophoresis pattern of serum proteins. Thus, nephrotoxic effects evoked by the antibiotic became evident about 48 hr after the injection, indicating that the time of onset of delayed toxicity of the compound is approximately 48 hr after dosing. As for the mechanism of the delayed toxic effects, evidence has been obtained for the formation of a toxic metabolite with an opened lactam ring, or an"acid compound"excreted in the rat urine. These findings support our previous inference, based on studies in mice.