Peak serum levels of gentamicin were varied in rats by administering a standard nephrotoxic dosage of 40 mg/kg per day in one (QD), two, or three (TID) daily doses. The QD animals had the highest peak serum levels but showed no appreciable increase of serum creatinine concentrations over a 10-day treatment period. The TID rats had the lowest peak serum levels, but, after 10 days of drug administration, the serum creatinine concentration (2.8 +/- 0.2 mg/100 ml, mean +/- SE) was significantly higher than in control rats (0.6 +/- 0.01 mg/100 ml) (P less than 0.001). After two days of gentamicin treatment, the renal concentration of gentamicin was 269 +/- 77 micrograms/g in the QD rats and 820 +/- 29 micrograms/g in the TID rats (P less than 0.001). In this rat model, the frequency of doses was a more important factor in the development of nephrotoxicity than the peak serum concentration of gentamicin. The results suggest that dose frequency should be considered when data from different laboratories are compared.

A rat model was utilized to compare the nephrotoxic potential of gentamicin and tobramycin. Gentamicin, 40 mg/kg per day, predictably produced renal failure and morphological evidence of proximal tubular necrosis over 14 days of treatment. An identical dosage of tobramycin was associated with only minimal morphological changes and normal concentrations of serum creatinine and blood urea nitrogen. Similar results were obtained even after the tobramycin dosage was tripled to 120 mg/kg per day. A decrease in urine osmolality, mechanism unknown, was observed in all aminoglycoside-treated rats, but the lowest osmolalities were found in the gentamicin-treated rats. According to both histological criteria and renal function measurements, gentamicin was more nephrotoxic than tobramycin in this animal model. This study was undertaken as a result of our interest in determining whether there were any important differences between the aminoglycoside antibiotics gentamicin and tobramycin. A review of the literature indicated only minor differences in in vitro antibacterial activity (1,6,8,14,20,31). Gentamicin is slightly more active against Serratia species, and tobramycin is slightly more active against isolates of Pseudomonas aeruginosa. In vivo animal studies of antibacterial activity again show similar degrees of activity, except that tobramycin is more active against P. aeruginosa infections (5,30). The pharmacokinetics of the two drugs in humans are felt to be virtually identical (9,12,22,28). Comparative toxicity studies of the effects of these two drugs in humans have not been reported.In a rat model, tobramycin was found to have a lower lethal dose than gentamicin (5). Tobramycin was found to have a lower lethal dose than gentamicin (5). Tobramycin was found to be less ototoxic than gentamicin in guinea pigs (2). Tobramycin was considered less nephrotoxic than gentamicin in rats on the basis of subtle but consistent histological changes and differences in drug-induced urinary lysosomal enzymes (12, 21). Since a clear difference in nephrotoxic potential would have clinical importance, studies were designed to more precisely detect any abnormalities in renal structure or function.Initially, a prospective randomized doubleblind study in humans was considered. A recent report describes such a study comparing gentamicin and amikacin (26). However, it appears virtually impossible to determine the incidence of aminoglycoside-induced nephrotoxicity in humans. There is no way for the investigator to separate disease-induced toxicity from drug-induced toxicity. Also, preillness measurements of renal structure and function are rarely available. Because of these concerns, we chose to use a rat model of aminoglycoside nephrotoxicity. Nephrotoxicity was quantitated by histological changes and alterations in renal fimction. The results demonstrate that, in this model, tobramycin is less nephrotoxic than gentamicin.MATERIALS AND METHODS Animals. Adult male Fischer 344 rats, weighing 175 to 275 g, were used. The rats were kept sing...

Reports from this laboratory of earlier studies have described acute tubular necrosis and azotemia in male Fischer rats given gentamicin over a 14 day period (1, 2). In the course of these studies, morphologic evidence of renal tubular regeneration was observed during the last 4 days of drug administration. The tubular regeneration was considered important in light of the results of Cuppage et al., who used the same rat model and an identical dosage regimen of gentamicin (3). They sacrificed the animals after 28 days of drug administration and found only minimal signs of toxicity as evidenced by scattered areas of necrotic tubular cells, some tubular regeneration, and in vitro impairment of renal oxidative metabolism (3). These results, viewed in light of our previous studies, led us to hypothesize that gentamicin-induced renal proximal tubular necrosis may be reversible despite continuous exposure to the drug for longer than one month. The experiments described below support this hypothesis.Materials and methods. Adult male Fischer 344 rats weighing 175-275 g were housed in metabolic cages, allowed free access to water, and fed a standard Purina diet, ad libitum. Screens were placed below the animal living spaces to avoid fecal or debris contamination of urine specimens. Rats were given either subcutaneous antibiotic-free saline or gentamicin in equal volumes (gentamicin, 40 mg/ml, was supplied by the Schering Corporation, Bloomfield, NJ). Rats were given 40 mg/kg per day of This study was supported by a grant from the National Institutes of Health, No. 1 RAI GM 22928-01, and a grant from the Portland Veterans Administration Hospital, MRIS No. 0901. Dr. Plamp was supported, in part, during these studies as a research fellow of the Oregon Heart Association. gentamicin in two equal divided doses at 8:OO A M and 4:OO PM.Student's two-tailed t test was used for statistical analysis of variance.Rats received gentamicin or saline for as long as 42 days. Drug-treated rats and control rats were sacrificed approximately 16-18 hr after their last doses on days 3, 7, 10, 14, 17, 21, 28, 34, and 42. At sacrifice, blood was obtained to determine blood urea nitrogen (BUN) and serum creatinine concentrations. The kidneys were then perfused with 0.