Effects of nephrotoxic beta-lactam antibiotics on the mitochondrial metabolism of monocarboxylic substrates.

UNLABELLED: The nephrotoxic beta-lactam antibiotics (beta-lactams) cephaloridine, cephaloglycin and imipenem are toxic to the mitochondrial transport and (secondarily) oxidation of succinate and other dicarboxylic substrates. However, compared to cephaloglycin, cephaloridine is minimally toxic to the mitochondrial uptake and uncoupled oxidation of the short-chain fatty anion butyrate. Further studies were therefore done to compare the early effects of nephrotoxic doses (300 mg/kg body weight) of imipenem, cephaloridine and cephaloglycin on the mitochondrial metabolism of three important monocarboxylic substrates, butyrate, valerate and pyruvate, in rabbit renal cortex. The following was found: 1) imipenen reduces the oxidation of all three monocarboxylates, within 0.5 to 1 hr after administration. 2) The respiratory toxicity of cephaloglycin is essentially the same as that of imipenem with all three substrates. 3) cephaloridine causes little or no toxicity to pyruvate or butyrate oxidation and is significantly less toxic than imipenem or cephaloglycin to valerate oxidation. 4) The effects of the three beta-lactams on butyrate and pyruvate uptake parallel their effects on butyrate and pyruvate oxidation.
CONCLUSIONS: Imipenem and cephaloglycin have essentially the same patterns of toxicity to the mitochondrial metabolism of all metabolic substrates that have been tested. Although cephaloridine has similar effects on dicarboxylic substrates, it is significantly less toxic to the mitochondrial metabolism of pyruvate and the short-chain fatty anions. It is proposed that cephaloridine's zwitterionic charge may restrict its ability to acylate monocarboxylic and other anionic carriers, resulting in less nephrotoxicity than might otherwise result from its uniquely high intracellular concentrations and singular ability among the toxic beta-lactams to produce oxidative injury.