EFFECT OF RENAL CATION-TRANSPORT INHIBITION ON CEPHALORIDINE NEPHROTOXICITY

The effects of various organic cations on the nephrotoxicity of the zwitterionic cephalosporin, cephaloridine, and other nephrotoxic agents were studied in the rabbit by determination of serum urea nitrogen and evaluation of renal cortical slice function as indicated by p-aminohippurate and tetraethylammonium accumulation and by gluconeogenesis using pyruvate as substrate. Pretreatment with a cationic transport inhibitor, Cyanine 863, 4 mg/kg, injected sc, 30 min before cephaloridine, 100 mg/kg, sc resulted in significantly greater nephrotoxicity compared to that observed after control cephaloridine treatment. Cyanine pretreatment did not affect the nephrotoxicity of cefazolin, 500 or 1000 mg/kg, a cephalosporin with no cationic group, suggesting that the effect of cyanine on cephaloridine nephrotoxicity was mediated through effects on cation transport. Cyanine pretreatment was also without effect on mercuric chloride nephrotoxicity, a finding which indicated that the effect of cyanine is not mediated by a nonspecific potentiation of nephrotoxic agents. Pretreatment with mepiperphenidol, 10 mg/kg, also enhanced cephaloridine nephrotoxicity while quinine, 75 mg/kg, had a slight effect and N-methylnicotinamide was essentially ineffective with respect to the alteration of cephaloridine nephrotoxicity. The administration of cyanine at short intervals after cephaloridine also increased nephrotoxicity. The results suggest that cation transport may play a role in the regulation of cortical cephaloridine concentrations and the resultant nephrotoxicity. Inhibition of a cationic transport step necessary for the exit of cephaloridine from the renal cortex is proposed as the mechanism responsible for the effects observed. © 1979.