Sex differences in nephrotoxic and gastrointestinal effects of phenylbutazone.

Male and female Wistar rats were used to study the sex differences in nephrotoxic, ulcerogenic and lethal effects of phenylbutazone (PBZ). In one series of experiments, male and female rats were given daily oral doses of 25, 125, 250, 400 and 500 mg PBZ/kg for 7 days to assess mortality, gross and microscopic lesions of the stomach, intestine and kidneys and to determine the PBZ effects on renal protein and glucose excretion. In another series of experiments, PBZ effects on renal gluconeogenesis and p-aminohippurate (PAH) accumulation in renal cortical slices were measured 12 h after administration of the same PBZ doses to male and female rats. Reduced glutathione (GSH) depletion and malondialdehyde (MDA) content in kidney cortex and liver were determined 2 h after a single administration of 250 mg PBZ/kg to male and female rats. To measure the effects of PBZ on blood urea nitrogen (BUN), male and female rats were given a single dose of PBZ (125 mg/kg) and were sacrificed at different time intervals, from 0 to 48 h. Gross and microscopic examination of the kidneys and gastrointestinal tract showed more pronounced renal and gastrointestinal lesions in surviving female than in male rats at the same doses. In PBZ treated male rats, BUN did not differ from control rats 48 h after PBZ administration. In female rats, BUN increased from 18 to 96 mg/100 ml 48 h after PBZ administration. After 7 days of PBZ treatment there was a greater increase of protein excretion in female than in male rats, but there were almost no sex differences in glucose excretion. Twelve hours after PBZ administration, renal PAH accumulation and gluconeogenesis were not different from controls in male rats but decreased in a dose-dependent fashion in females. A significant depletion of GSH and a significant increase in MDA content in liver and renal cortex occurred in female but not in male rats. In conclusion, the PBZ treatment was associated with nephrotoxic and gastrointestinal effects which could be detected earlier and were greater in female than in male rats.