CEPHALOSPORIN AND CARBACEPHEM NEPHROTOXICITY - ROLES OF TUBULAR CELL UPTAKE AND ACYLATING POTENTIAL

Three beta-lactams, desacetylcephaloglycin, ampicillin, and loracarbef , were studied to lest a hypothesis derived from retrospective analysi s of previously studied cephalosporins: that beta-lactam nephrotoxicit y develops in approximate proportion to tubular cell antibiotic concen trations and lactam ring reactivities. Concentrations of each beta lac tam (and inulin) in rabbit renal cortex and serum were measured at the end of 0.5-hr infusions of 100 mg antibiotic/kg body weight and 0.5 t o 0.67 hr later. Total cortical AUCs (total areas under the curve of c oncentration and time in renal cortex) and transported cortical AUCs ( total minus inulin-space beta lactam) were calculated from these measu rements. Reactivities, determined by the rate constants of lactam-ring opening at pH 10, were taken from the literature. Nephrotoxicity was quantified by grades of proximal tubular cell necrosis and by serum cr eatinine concentrations 2 days after infusion of 100-1500 mg/kg of the antibiotics. Desacetylcephaloglycin was slightly less nephrotoxic tha n cephaloglycin; the AUCs, reactivities, and toxicities of these two c ephalosporins fit the proposed model, particularly when allowance is m ade for hepatic and renal deacetylation of cephaloglycin. The very low AUCs, limited reactivity, and absence of nephrotoxicity of ampicillin also fit the model. Loracarbef had a transported AUC less than three times, and reactivity one-thirtieth, those of cefaclor, respectively. Although only at 1500 mg/kg, loracarbef was significantly more nephrot oxic than cefaclor. If the reactivity of loracarbef with its targeted bacterial proteins, which is essentially the same as that of cefaclor, is considered instead of the base hydrolysis rate constant, then lora carbef also fits the model. By the same analysis, the comparatively hi gh in vitro stability of other carbacephems, although pharmaceutically convenient, may not limit their nephrotoxicity.