RENAL TUBULAR TRANSPORT AND NEPHROTOXICITY OF BETA-LACTAM ANTIBIOTICS- STRUCTURE-ACTIVITY-RELATIONSHIPS

Several of the cephalosporin and carbapenem antibiotics produce acute renal failure when given in large single doses. Antibiotic concentrati ons in the tubular cell, determined by the net effects of contralumina l secretory transport and subsequent movement across the luminal membr ane, make the proximal tubule the sole target of injury, and are impor tant determinants of the nephrotoxic potentials of different beta-lact ams in different animal species. At least three molecular mechanisms o f injury have been shown with cephaloridine, the most widely studied n ephrotoxic beta-lactam: (1) lipid peroxidation, (2) competitive inhibi tion of mitochondrial carnitine (zwitterionic) transport and fatty aci d oxidation, and (3) acylation and inactivation of tubular cell protei ns, most thoroughly evaluated with mitochondrial anionic substrate tra nsporters. The first two of these injuries are dependent upon one or b oth of cephaloridine's side group substituents, which are not present on the other nephrotoxic cephalosporins or carbapenems. It is not surp rising, therefore, that only toxicity to mitochondrial anionic substra te carriers has been found in studies of the other beta-lactams. Howev er, the several effects of cephaloridine on the tubular cell indicate a potential for different mechanisms of attack on different molecular targets. Continuing studies of the effects of existing and newly devel oped beta-lactams are likely to identify further nephrotoxic mechanism s of this complex and rapidly growing group of antimicrobials.