Influence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin

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Abstract
Multiple factors may modify the pharmacokinetics of aminoglycosides and increase their nephrotoxic potential. In this study, we investigated the influence of Escherichia coli endotoxin on the renal handling of several aminoglycosides and one cephalosporin. Drug levels in the renal parenchyma, as well as several parameters of renal function and histology, were compared in rats treated with endotoxin (0.25 mg/kg) and normal rats treated with either gentamicin (10 mg/kg), netilmicin (10 mg/kg), tobramycin (10 mg/kg), amikacin (50 mg/kg), or cephalothin (100 mg/kg). Blood pressure and pulse rate were recorded. Endotoxin was associated with a decrease in the half-life and in the apparent volume of distribution of gentamicin. The endotoxin-injected animals accumulated significantly (P less than 0.05) more aminoglycosides in their kidneys than the normal animals. The amount of cephalothin recovered in the renal parenchyma was identical in both groups. Slight decreases in the glomerular filtration rate and renal plasma flow were observed after endotoxin treatment. Blood pressure and cardiac frequency were minimally affected by endotoxin. No histological lesions were observed by light microscopy in animals receiving endotoxin. Thus, endotoxin modifies the renal handling of aminoglycosides in the absence of any major physiological disturbance or histological change. By increasing the total amount of drug within the kidneys, endotoxin might increase the nephrotoxic potential of aminoglycosides.