EFFECTS OF NEPHROTOXIC BETA-LACTAM ANTIBIOTICS ON THE MITOCHONDRIAL METABOLISM OF MONOCARBOXYLIC SUBSTRATES

The nephrotoxic beta-lactam antibiotics (beta-lactams) cephaloridine, cephaloglycin and imipenem are toxic to the mitochondrial transport an d (secondarily) oxidation of succinate and other dicarboxylic substrat es. However, compared to cephaloglycin, cephaloridine is minimally tox ic to the mitochondrial uptake and uncoupled oxidation of the short-ch ain fatty anion butyrate. Further studies were therefore done to compa re the early effects of nephrotoxic doses (300 mg/kg body weight) of i mipenem, cephaloridine and cephaloglycin on the mitochondrial metaboli sm of three important monocarboxylic substrates, butyrate, valerate an d pyruvate, in rabbit renal cortex. The following was found: 1) Imipen em reduces the oxidation of all three monocarboxylates, within 0.5 to 1 hr after administration. 2) The respiratory toxicity of cephaloglyci n is essentially the same as that of imipenem With all three substrate s. 3) cephaloridine causes little or no toxicity to pyruvate or butyra te oxidation and is significantly less toxic than imipenem or cephalog lycin 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 esse ntially the same patterns of toxicity to the mitochondrial metabolism of all metabolic substrates that have been tested. Although cephalorid ine has similar effects on dicarboxylic substrates, it is significantl y 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 an ionic carriers, resulting in less nephrotoxicity than might otherwise result from its uniquely high intracellular concentrations and singula r ability among the toxic beta-lactams to produce oxidative injury.