Acute toxicity of ranitidine and its metabolite in mice, rats and rabbits, and subacute oral toxicity of ranitidine in rats

Abstract

Acute and subacute toxicities of ranitidine hydrochloride, a new histamine H2-receptor antagonist, and acute toxicity of ranitidine N-oxide, a metabolite of ranitidine hydrochloride, were investigated. The results are summarized as follows: (1) Oral, intravenous, subcutaneous, intraperitoneal and intramuscular LD50 values of ranitidine hydrochloride in 5- and 12-weeks old mice and rats and 12-weeks old rabbits were ranged from ca. 60 mg/kg (12-weeks old male mice, i.v.) to 6610 mg/kg (12-weeks old male rats, p.o.). In comparison of the LD50 values, it was revealed that female rats were more sensitive to the drug than males in the case of oral administration. (2) A single intravenous injection with ranitidine N-oxide at a dose of 1000 mg/kg, induced no lethal cases in mice, indicating that the N-oxide has very low toxicity in a comparison with that of ranitidine hydrochloride. (3) In the subacute toxicity test, male and female rats were orally administered with ranitidine hydrochloride for 35 days. Dose dependent changes such as increase in liver weight and water consumption, decrease in spontaneous movement and others were induced at doses of more than 500 mg/kg/day in females and 1000 mg/kg/day in males. These results indicate that the no effects were observed at levels of 250 mg/kg/day in females and 500 mg/kg/day in males. In the recovery test, however, no marked changes were observed in the rats which had been administered at 1000 and 2000 mg/kg/day for 35 days.