Abstract

Attempts to demonstrate net renal secretion of the antibiotic cephaloridine in mammals have been unsuccessful. Nevertheless, the acute proximal tubular necrosis produced by the drug can be prevented by prior administration of a variety of organic acid transport inhibitors. Studies were performed which confirmed the protective effect of probenecid against cephaloridine's nephrotoxicity its the rabbit. Renal uptake of cephaloridine was then studied in rabbits by giving single subcutaneous injections of the drug and measuring its concentration in serum, renal cortex and medulla 30 minutes later. Cortex/serum ratios (C/S) of cephaloridine were 12.2 ± S.E. 0.8 (10 animals) at doses of 100 mg/kg and 10.6 ± 0.6 (10) at doses of 25 mg/kg. These ratios were strikingly greater than those of inulin [C/S inulin = 1.5 ± 0.2 (5)]. Thus, cortical cephahoridine content was significantly greater than than can be accounted for by glomerular filtration alone. Prior administration of probenecid (100 mg/kg) to animals receiving 100 mg/kg of cephaloridine reduced C/S to 1.2 ± 0.1 (5). Administration of benzylpenicillin, given in increasing doses (100, 350 and 1000 mg/kg) to animals receiving 100 mg/kg of cephaloridine, resulted in decreases of C/S (7.0,2.9 and 1.1, respectively), suggesting a competitive inhibition of cortical cephaloridine uptake. Medulla/serum (M/S) cephaloridine concentrations were consistently lower than those of inulin [M/S inulin = 4.8 ± 0.6 (5)] and were significantly decreased by prior mannitol infusion, but they were unaffected by probenecid or benzylpenicillin. It is hypothesized that the renal cortical uptake and proximal tubular toxicity of cephaloridine are related to a carrier-mediated transport system. Possible explanations why significant net cephaloridline secretion does not occur in the mammalians kidney are discussed.