Acute and subchronic toxicity of a nonsulfhydryl angiotensin-converting enzyme inhibitor.
Acute and 1-month toxicity studies with SCH 31846, a nonsulfhydryl anti-hypertensive agent which acts by inhibiting angiotensin-converting enzyme, were initiated to evaluate its toxicity. The oral LD50s in mice and rats were approximately 1.8 and 2.5 g/kg, respectively, while the iv LD50 was approximately 450 mg/kg in mice and 150 mg/kg in rats. Signs of acute toxicity in rats and mice included salivation, hypoactivity, ataxia, prostration, and convulsions. In a 1-month dog study at oral doses of 25, 75, or 150 mg/kg, there was a dose-related increase in emesis between 1 and 2 hr after dosing. Absorption studies showed peak blood concentrations occurring in dogs between 0.3 and 1 hr after dosing. No other noteworthy antemortem changes were observed. In a 1-month rat study at oral doses of 30, 180, or 600 mg/kg, the hematocrit and hemoglobin values of the 600 mg/kg-dosed female rats were slightly but significantly (p less than 0.05) decreased and the blood urea nitrogen was slightly but significantly (p less than 0.05) increased in all SCH 31846-dosed male rats and the 600 mg/kg-dosed female rats. Absorption studies in male rats at doses of 30, 180, and 600 mg/kg indicate that SCH 31846 is well absorbed in rats. The 150 mg/kg-dosed dogs and the 180- and 600 mg/kg-dosed rats had a slight increase in the number of renin-containing granules in the renal juxtaglomerular cells. No other compound-related microscopic changes were observed. These data are similar to data reported for Captopril and suggest that in the dog and rat the toxicity of ACE inhibitors is not dependent upon the presence or absence of a sulfhydryl group.
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001806:Blood Urea Nitrogen; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D007211:Indoles / Q000008:administration & dosage / Q000633:toxicity*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D006454:Hemoglobins; D007211:Indoles; C038812:Indolapril