Effectiveness and toxicity of gentamicin in an experimental model of pyelonephritis: Effect of the time of administration

Temporal variations in the renal toxicity of aminoglycosides have been repo rted for experimental animals as well as for humans. In fact, maximal renal toxicity of aminoglycosides was observed when the drug was given during th e rest period, while a lower toxicity was observed when the drug was inject ed 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 ca rried out with female Sprague-Dawley rats (185 to 250 g). They had free acc ess to food and water: throughout the study and were maintained on a 14-h l ight-10-h dark cycle. Animals were divided into four groups corresponding t o the respective time of induction of pyelonephritis and treatment: 0700, 1 300, 1900, and 0100 h. Pyelonephritis was induced by a direct inoculation o f Escherichia coli (10(7) to 10(8) CFU) in the left kidney. Animals were tr eated 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, 13 00, 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 effica cy, evaluated by the log CFU per gram of tissue and by the percentage of st erilized kidneys, was also higher when gentamicin was administered at: 0100 h. The beta-galactosidase and the N-acetyl-beta-D-glucosaminidase activiti es were significantly higher in urine of rats given gentamicin at 1300 h th an in urine of rats treated at another time of day (P < 0.05). Gentamicin i njected at 1300 h induced a significantly greater increase of [H-3]thymidin e incorporation into DNA of renal cortex (P < 0.01), a significantly greate r inhibition of sphingomyelinase activity (P < 0.05), and significantly mor e histopathological lesions than the same dose injected at another time of the day. Creatinine and blood urea nitrogen levels in serum were significan tly 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 t oxicity and the effectiveness of gentamicin, the drug being more effective and less toxic when injected during the activity period of the animals.