新鎮痛消炎薬4-Ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101)のラットに対する毒性に関する病理学的考察

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By using male and female JCL:SD rats, the subacute toxicity and recovery from toxic phenomena were tested on M73101, which was newly developed as an analgesic and anti-inflammatory drug. The drug was compulsively administered perorally in doses of 250, 500 and 1,000 mg/kg/day for six weeks. One female rat in the highest dose group died from intoxication. None of the animals of both sexes given 250mg or 500mg died during the experimental periods. No other toxic signs than an increased salvation were observed in the rats of these groups. In the groups of 1,000 mg/kg/day, a slight inhibition was induced in the growth curve and in the food efficiency. An increase in water consumption was observed in all of the medicated groups, being more remarkable in female than in male. In the highest dose groups, male rats showed proteinuria, while female rats showed an increase in urinary output. There were no significant changes in the histological appearances of blood and bone marrow. As to biochemical profiles of serum, the highest dose groups showed an increase in the albumin-globulin ratio and activity of GPT in both sexes, and an increase in alkaline phosphatase activity and the contents of cholesterol and neutral fat was observed only in female rats. Pathological examinaton revealed a dose-dependent increase in liver weight and a hypertrophy of hepatocytes due to proliferation of smooth endoplasmic reticulum. These changes were more intense in female than in male rats suggesting the presence of a sex difference in the effect of the drug. An increase in the weight of kidneys was also noted. Histologically, swelling and vacuolation of proximal tubular epithelial cells were observed, and single cell degeneration or necrosis was also found electron-microscopically. A conspicuous change in the gastro-intestinal tracts was ulcer formation due to swelling and subsequent desquamaton of mucous epithelial cells; however, the ulcers did not develop beyond lamina muscularis mucosae (grade I ulcus or erosion). In the recovery experiments, the symptoms and pathological changes mentioned above almost disappeared one month after the cessation of the drug administration, except that a hypertrophy of hepatocytes still remained histologically to some extent in female. It was concluded that the target organs of M73101 were regarded virtually to be the liver, kidneys and gastro-intestinal tracts. The largest non-toxic dose of the drug was considered to be 125 mg/kg body weight/day in male and 30-60 mg/kg body. weight/day in female rats (according to a supplement experiment). Furthermore, it was suggested that the greatest safety dose was 250 mg/kg body weight/day in male, while it was 125mg/kg in female rats,
日本トキシコロジー学会の論文
1979-05-15

新鎮痛消炎薬4-Ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101)のラットに対する毒性に関する病理学的考察

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