Abstract
Cefotetan (CTT, YM09330), cefazolin and cephalothin were intravenously dosed to female rabbits of the New Zealand White strain to study their nephrotoxicity. The dose levels used were 600mg/kg and 1, 200mg/kg, and each dose was given to 6 animals. Eight animals receiving a physiological saline were used as controls. Following a single treatment, all animals were subjected to clinical laboratory tests, and they were killed on day 3 postdosing, followed by pathological examinations.
Cefotetan: Anorexia occurred at both 600mg/kg and 1, 200mg/kg, but no deaths were found. Plasma urea nitrogen and creatinine were not increased. Although glycosuria was not detected in any animals, proteinuria was found in one animal receiving 1, 200mg/kg. Macroscopic examination of the kidneys disclosed a gray nodule in an animal receiving 1, 200mg/kg and small cysts in another animal receiving the same dose. Small cysts were also found in an animal receiving 600mg/kg. Histological examination of the kidneys showed that the gray nodules seen in the animal receiving 1, 200mg/kg was nephroblastoma. An animal receiving 600mg/kg showed necrosis on the proximal tubular epithelium.
Cefazolin: An animal receiving 1, 200mg/kg died about 6 hours after dosing. Anorexia occurred at both 600mg/kg and 1, 200mg/kg. Plasma urea nitrogen and creatinine were increased at 1, 200mg/kg and glucose and protein were detected in the urine in some animals receiving 600mg/kg and 1, 200mg/kg. Macroscopic examination of the kidneys disclosed colour changes of the organs as well as their enlargement in all animals receiving 1, 200mg/kg. Small cysts were also observed in some animals. In 3 animals receiving 600mg/kg, densely packed gray microspots were found. Histological examination of the kidneys showed that necrosis occurred in the proximal tubular epithelium in a dose dependent fashion.
Cephalothin: Mild anorexia was seen at both 600mg/kg and 1, 200mg/kg. Proteins were detected in the urine in an animal receiving 1, 200mg/kg, but no abnormalities were found in plasma bio-chemical tests. The kidneys were also macroscopically examined. The kidneys were coloured yellow-brown in 2 animals receiving 600mg/kg, and small cysts were present in these animals. However, no drug related abnormalities were detected during histological examination of the kidneys.
Although some histological abnormalities were found in the kidneys of the animals receiving cefotetan, these abnormalities were not dose-related, and thus, in conclusion, the renal toxicity of the drug is comparable to that of cephalothin, and considerably weaker than that of cefazolin in rabbits.
