CHARACTERIZATION OF THE HIGH-SENSITIVITY OF RABBITS TO THE EFFECTS OFTCV-116, AN ANGIOTENSIN-II RECEPTOR ANTAGONIST

A high incidence of maternal toxicity in rabbits characterized by urem ia and death was observed when TCV-116, a novel angiotensin II subtype -1 (AT1) receptor antagonist, was orally administered to pregnant rabb its at dosage levels of 3 mg/kg/day or more. The effects of TCV-116 on blood pressure in nonpregnant or male rabbits and rats and on blood c hemistry, renal circulation, and plasma renin activity in nonpregnant or male rabbits were examined to characterize the toxicity in rabbits. In a 2-week repeated dose study, most nonpregnant female rabbits rece iving 3 or 100 mg/kg/day died or were sacrificed in a moribund state, indicating that toxicity could be caused independently of pregnancy. W hen these rabbits became moribund, marked hypotension, accompanied by increases in plasma concentrations of urea nitrogen, creatinine, and p otassium, was observed, suggesting uremia. In a single-dose study, blo od pressure in rabbits was decreased after administration of 10 or 100 mg/kg of TCV-116, and the hypotension was more marked and sustained t han that in rats, as was the case with 30 mg/kg of enalapril. The sust ained pharmacological effect in rabbits was also confirmed with regard to decreases in effective renal plasma flow and the glomerular filtra tion rate and increased plasma renin activity. Species differences in the hypotensive effect and mortality could not be explained by toxicok inetic data for the active metabolite of TCV-116 in various species, w hich supported a possibility that the differences in toxicity may be r elated to the species difference in sensitivity to the pharmacological effect of TCV-116. We conclude that the specific maternal toxicity of TCV-116 in rabbits may be mainly due to the higher sensitivity of rab bits to the pharmacological effects and is caused by marked and sustai ned hypotension resulting in the decrease in glomerular filtration rat e, uremia, and death. (C) 1997 Society of Toxicology.