Cephalosporin nephrotoxicity. Transport, cytotoxicity and mitochondrial toxicity of cephaloglycin.
The cephalosporin antibiotics are secreted by the renal organic anion transport system. Several of them, including cephaloridine and caphaloglycin, produce a proximal renal tubular necrosis which can be prevented by inhibitors of organic anion transport. Although cephaloridine is actively transported into the tubular cell at the antiluminal side like other cephalosporins, it undergoes a limited rate of subsequent movement across the luminal membrane into the tubular fluid. The very high intracellular concentrations that result from this unusual process are believed to contribute to the significant toxicity of cephaloridine. Cephaloglycin is at least as toxic, but is secreted more normally across the proximal tubular cell. For this reason, studies were undertaken to evaluate the cytotoxicity, cortical concentrations and mitochondrial respiratory toxicity of this cephalosporin in the rabbit kidney. A dose of 100 mg/kg of caphaloglycin produces as much damage as does 150 mg/kg of cephaloridine. The steady-state cortex-to-serum concentration ratio of cephaloglycin, 5.6 +/- 0.8 S.E. (n = 5), is significantly lower (P < .001) than the corresponding measurement for cephaloridine, 121.9 +/- 1.2 (n = 7), and is not significantly different from that of p-aminohippurate. In further contrast to cephaloridine, the cortical concentration of cephaloglycin declines substantially, from 930 +/- 112 (n = 5) to 297 +/- 46 (n = 5) micrograms/g of wet tissue, over the first hour after cessation of infusion (P < .001) and is essentially unmeasurable by 2 hr. The fact that there is not the prolonged intracellular trapping of cephaloglycin that is seen with cephaloridine leads to the conclusion that the former must either bind more strongly to its target receptor or produce a more irreversible insult than does the latter cephalosporin. Several lines of evidence are presented which support this hypothesis. The most important of these are that cephaloglycin is cumulatively nephrotoxic, whereas cephaloridine is not, and that the in vivo toxicity of cephaloglycin to cortical mitochondria, unlike that of cephaloridine, is not significantly diminished by the mitochondrial isolation process. This very early in vivo respiratory toxicity of cephaloglycin and the lack of significant similar toxicity of cephalexin provide new evidence that the effect on mitochondria may have a pathogenic role in cephalosporin nephrotoxicity.
D000818:Animals; D002507:Cephaloglycin / Q000378:metabolism / Q000633:toxicity*; D002509:Cephaloridine / Q000633:toxicity; D005260:Female; D007668:Kidney / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects*; D011339:Probenecid / Q000494:pharmacology; D011817:Rabbits
D002509:Cephaloridine; D002507:Cephaloglycin; D011339:Probenecid