A subchronic study of the toxicity of an orally administered benzoquinolizinyl derivative in the rat and dog.

The subchronic toxicity of the trans isomer of N-(1,3,4,6,7-hexahydro-11bH-benzo[a] quinolizin-2-yl) propionanilide hydrochloride (TR2379), a new antihypertensive agent, was studied in rats and dogs. TR2379 was well tolerated for 13 weeks at daily p.o. doses up to 200 mg/kg in the rat and 70 mg/kg in the dog. However, severe toxic manifestations, including death, were elicited in the rat at 820 mg/kg and in the dog at 160 mg/kg. Toxicity in both species was characterized by a reduction in body weight gain and an increase in the weight of several organs, (liver, heart, kidneys, adrenals, and thyroids). Serum alkaline phosphatase, which was not assayed in the rat, was markedly increased in the dog. Microscopic examination of the various tissues revealed no evidence of organ pathology in either species.

Influence of a benzoquinolizinyl derivative on serum and hepatic alkaline phosphatase activity in the dog and rat.

Oral administration of 100 mg/kg of TR2379, N-(1,3,4,6,7-hexahydro-11bH-benzo[a]quinolizin-2-yl) propionanilide hydrochloride, for 20--29 days to 6 dogs resulted in significant elevations of alkaline phosphatase (AP) activity in serum and in liver microsomes. Results of biochemical and histochemical experiments revealed that the liver was the sole source of the increased AP activity but there was no evidence of liver damage. The subchronic (7-35 day) p.o. administration of TR2379 at 820 mg/kg to 20 rats did not produce elevation of AP activity in serum or liver. Relative liver weights (g/100 g body wt) of rats receiving TR2379 were significantly increased during the 2nd week and thereafter. The results of these studies suggest that high doses of TR2379 induce protein synthesis in dog and rat liver and induce AP activity in the dog but not in the rat. The elevation of AP in the dog is not considered to have toxicologic implications.