TEMPORAL CHANGES OF PHARMACOKINETICS, NEPHROTOXICITY, AND SUBCELLULAR-DISTRIBUTION OF TOBRAMYCIN IN RATS

The present study was designed to determine the temporal changes in to bramycin nephrotoxicity during the dark and the light periods of the d ay and to look for the mechanisms of such changes. Female Sprague-Dawl ey rats (9 to 11 weeks old) were housed in a 14-h-light-10-h-dark cycl e (lights on 0600 to 2000 h). A bolus of tobramycin (60 mg/kg of body weight) was intravenously injected into a first group of 15 rats, at e ither 1400 or 0200 h. Six blood samples were taken from each rat, 30 t o 210 min after the bolus injection. The total clearance of the drug w as reduced during the rest period (1400 h) of rats compared with the a ctivity period (0200 h) (P = 0.0007). Another group of 99 rats was giv en intraperitoneally a single dose of tobramycin (40 mg/kg), and renal cortices were collected 2 to 222 h after injection. The cortical drug levels were always higher in animals injected at 1400 h than in those injected at 0200 h. A last group of 32 rats was used in the studies o f tobramycin (30 mg/kg/day, once daily for 10 days, intraperitoneally) nephrotoxicity and subcellular distribution. Weight gain in the rats receiving tobramycin (both 1400 and 0200 h) was significantly (P = 0.0 28) less than that in the controls. Nephrotoxicity, indicated by the i ncorporation of [H-3]thymidine into cortical DNA and urinary excretion of N-acetyl-beta-D-glucosaminidase, was significantly higher in anima ls treated at 1400 h than in those treated at 0200 h. No difference in the subcellular distribution of tobramycin was observed. The data ind icate that the reduction in the clearance of tobramycin during the res t period is in part responsible for the higher nephrotoxicity in rats.