Temporal variations in the renal toxicity of
aminoglycosides have been reported for experimental animals as well as for humans. In fact, maximal renal toxicity of
aminoglycosides was observed when the
drug was given during the rest period, while a lower toxicity was observed when the
drug was injected during the activity period. The aim of the present study was to evaluate temporal variations in the effectiveness and renal toxicity of
gentamicin in an experimental model of
pyelonephritis in rats. The experiments were carried out with female Sprague-Dawley rats (185 to 250 g). They had free access to food and water throughout the study and were maintained on a 14-h light-10-h dark cycle. Animals were divided into four groups corresponding to the respective time of induction of
pyelonephritis and treatment: 0700, 1300, 1900, and 0100 h.
Pyelonephritis was induced by a direct inoculation of Escherichia coli (10(7) to 10(8) CFU) in the left kidney. Animals were treated for 3 and 7 days with a single daily dose of
gentamicin (20 and 40 mg/kg of
body weight, respectively) or saline (NaCl, 0.9%) at either 0700, 1300, 1900, or 0100 h. Animals treated at 0100 h for 3 days with
gentamicin (20 mg/kg) showed a significantly lower number of bacteria in their kidneys than did all other groups (P < 0.01). After 7 days of treatment, the efficacy, evaluated by the log CFU per gram of tissue and by the percentage of sterilized kidneys, was also higher when
gentamicin was administered at 0100 h. The
beta-galactosidase and the
N-acetyl-beta-D-glucosaminidase activities were significantly higher in urine of rats given
gentamicin at 1300 h than in urine of rats treated at another time of day (P < 0.05).
Gentamicin injected at 1300 h induced a significantly greater increase of [3H]
thymidine incorporation into
DNA of renal cortex (P < 0.01), a significantly greater inhibition of
sphingomyelinase activity (P < 0.05), and significantly more histopathological lesions than the same dose injected at another time of the day.
Creatinine and blood
urea nitrogen levels in serum were significantly higher (P < 0.05) and the
creatinine clearance was significantly lower (P < 0.05) when
gentamicin was injected at 1300 h than when it was injected at another time of day. Our data suggest temporal variations in both the toxicity and the effectiveness of
gentamicin, the
drug being more effective and less toxic when injected during the activity period of the animals.