NEPHROTOXICITY OF LOW-DOSES OF TOBRAMYCIN IN RATS - EFFECT OF THE TIME OF ADMINISTRATION

The circadian and the circannual variations of the nephrotoxicity of t obramycin were studied in female Sprague-Dawley rats. Animals were mai ntained on a light-dark period of 14/10 hrs (light on: 06h00 to 20h00) . They were injected once daily for 4 and 10 days with saline or tobra mycin at a dose of 40 mg/kg/day i.p. at either 08h00, 14h00, 20h00 and 02h00, in April 1991, July 91, October 91, January 92. In April 91, t obramycin injected at 14h00 during 10 days induced a significant incre ase of [H-3]-thymidine incorporation into DNA of renal cortex as compa red to other groups (p < 0.01): toxicity was highest at 14h00 and lowe st at 02h00. No temporal change was observed in the renal cortical acc umulation of tobramycin, and in serum creatinine after the 4 or 10 day s of treatment. In experiments done in April, July and October 1991 an d in January 1992, no circannual variation was found in tobramycin cor tical levels but peaks of toxicity were observed at 02h00 in April and October 1991 and at 14h00 in July 1991 and January 1992. There was no linear correlation between the toxicity and the tobramycin accumulati on in the renal cortex (r = 0.21). The data suggest that the circadian changes in tobramycin toxicity are due to temporal changes in the sus ceptibility of renal cells to tobramycin.