Thienamycin nephrotoxicity. Mitochondrial injury and oxidative effects of imipenem in the rabbit kidney.

The nephrotoxic cephalosoprins cephaloridine and cephaloglycin both produce mitochondrial respiratory toxicity in renal cortex. Recent work has provided evidence that this respiratory toxicity is caused by acylation and inactivation of mitochondrial anionic substrate transporters. While cephaloridine also causes significant lipid peroxidative injury in cortical mitochondria and microsomes, cephaloglycin causes little or no oxidative damage under identical conditions. The recently released thienamycin antibiotic, imipenem, like the toxic cephalosporins, produces acute proximal tubular necrosis which can be prevented completely by prior administration of probenecid. The ability of imipenem to block mitochondrial substrate uptake and respiration and produce oxidative changes has not been examined. We therefore evaluated the effects of imipenem in rabbit renal cortex on the following: (1) mitochondrial function [respiration with and uptake of succinate, and uptake of ADP]; and (2) evidence of oxidative change [depletion of reduced glutathione (GSH), production of oxidized glutathione (GSSG), and production of lipid peroxidative injury, as reflected in microsomal conjugated dienes (CDs)]. The mitochondrial effects of 300 mg/kg body wt of imipenem, given i.v. 1 and 2 hr before killing the animals, were comparable to those of the nephrotoxic cephalosporins. There was significant reduction of respiration with, and unidirectional uptake of, succinate at both times, while mitochondrial ADP transport was comparatively unaffected. Imipenem also depleted GSH and increased GSSG and CDs at 1 hr. These effects, however, were considerably smaller than those of a comparably nephrotoxic dose of cephaloridine, and this evidence of oxidative stress had resolved by 2 hr. We conclude that imipenem and the nephrotoxic cephalosporins have similar effects on mitochondrial substrate uptake and respiration, but differ significantly in their production of oxidative injury.