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), tobramyin (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 gentamnicin. The endotoxin-injected animals accumulated significantly (P < 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.Previous studies done in our laboratory revealed that the intrarenal distribution of gentamicin was disturbed in experimental pyelonephritis due to Escherichia coli (5). A greater accumulation of drug was observed in the cortex and medulla of pyelonephritic animals than in the kidneys of noninfected animals. Pyelonephritic kidneys were also shown to be more susceptible tp'the nephrotoxic potential of gentamicin than normal kidneys (2). Pyelonephritic animals treated with gentamicin showed signs of renal damage which were more striking than those observed in normal treated rats. We considered the possibility that endotoxin liberated during antibiotic therapy (13, 25) might have disturbed the intrarenal pharmacokinetics of gentamicin and acted concomitantly with gentamicin on tubular cells to potentiate the toxicity of this antibiotic. The purpose of the present study was to evaluate the influence of endotoxin on the intrarenal distribution of aminoglycosides.MATERIALS AND METHODS Experimental model: distribution studies. Female SpragueDawley rats weighing 175 to 200 g were used for all experiments. Sixteen groups of 5 to 11 animals were anesthetized by a single intraperitoneal injection of sodium pentobarbital (45 mg/kg), followed 2 h later by a second dose of 20 mg/kg. Four animals, two controls and two endotoxintreated rats, were used in parallel each day. Catheters were inserted into the right jugular vein for infusion of solutions. E. coli 0127:B8 endotoxin (0.25 mg/kg; Difco Laboratories, Detroit, Mich.) or normal saline was infused intr...