Ranitidine hydrochlorideのビーグルにおける経口投与毒性試験

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  • ORAL TOXICITY STUDIES OF RANITIDINE HYDROCHLORIDE IN BEAGLES

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Ranitidine, a histamine H2-receptor antagonist was orally administered to beagles, and acute, five-week subacute, 26-week chronic toxicity and recovery studies were carried out. I. Acute toxicity Ranitidine. in the single doses of 1, 000, 1, 500, 2, 500, 3, 000 or 3, 500mg/kg was administered to one male and one female beagles at each dose. Vomiting, tremor and motor ataxia were found shortly after the administration. However, no deaths occurred even at the highest level of 3, 500mg/kg, with the exception of the male at level of 3, 000 mg/kg. Levels higher than 3, 500 mg/kg were not studied because of extremely severe vomiting. II. Five-week subacute toxicity 1) Ranitidine was administered to three male and three female beagles at the dose level of 40, 80, 160 or 320 mg/kg/day for 5 weeks, but no death occured at any level. No sign of abnormality was seen at 40 mg/kg/day. 2) In the 80 mg/kg/day group, no sign was seen except for salivation. In the groups which received 160 mg/kg/day or more, salivation, vomiting and soft feces appeared, and in males, significant decreased in erythrocyte counts and hematocrit and hemoglobin values were noted in association with minute bleeding in the lower digestive tract accompanied by soft feces. In the 320 mg/kg/day group, food intake decreased. growth of body weight was suppressed and minor tarry feces were noted sporadically. In the males in this group, decreases in leukocyte count, hematoctit and hemoglobin values and serum protein and increases in platelet and reticulocyte counts were noted, in association with minute bleeding in the lower digestive tract. 4) In the histopathology, no notoworthy chatige was noted except for partial atrophy and erosion of the colonic mucosa in one female at 80 mg/kg and erosion of the colonic mucosa in one male at 320 mg/kg. 5) The 'maximum non-toxic' level of ranitidine was estimated to be approximately 40 mg/kg/day which corresponds to 7-8 times higher dose than the clinical daily dose for humans. III. Twenty-six week chronic toxicity 1) Ranitidine was orally administered to three male and three female beagles at 40, 80 and 160 mg/kg once a day for 26 weeks. Subdequently, in both the 80 and 160 mg/kg groups, a 30-day recovery study was carried out. No deaths occurred. In the 40 mg/kg group, no abnormality was noted. 2) At 80 mg/kg or more, salivation, vomiting and soft feces were seen just as in the subacute toxicity study. 3) In the 160 mg/kg group, decrease in food intake, suppression of body weight gain and occult blood in the feces were observed. In association with this bleeding, decreases in erythrocyte count and in hematocrit and hemoglobin values were noted in the males, but no other noteworthy change was observed. 4) In the histopatholgy either, no noteworthy change was found. 5) In electron microscopic observation, no noteworthy change was noted with the exception of a slight change in the tapetum in the 160 mg/kg group. 6) All the above-mentioned changes disappeared after withdrawal of the test drug: 7) The 'no observable effect' level of ranitidine was estimated to be approximately 40mg/kg/day which corresponds to 7-8 times higher dose than the clinical daily dose for humans.

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