Characterization of the high sensitivity of rabbits to the effects of TCV-116, an angiotensin II receptor antagonist.
A high incidence of maternal toxicity in rabbits characterized by uremia and death was observed when TCV-116, a novel angiotensin II subtype-1 (AT1) receptor antagonist, was orally administered to pregnant rabbits 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 chemistry, 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 receiving 3 or 100 mg/kg/day died or were sacrificed in a moribund state, indicating that toxicity could be caused independently of pregnancy. When these rabbits became moribund, marked hypotension, accompanied by increases in plasma concentrations of urea nitrogen, creatinine, and potassium, was observed, suggesting uremia. In a single-dose study, blood pressure in rabbits was decreased after administration of 10 or 100 mg/kg of TCV-116, and the hypotension was more marked and sustained than that in rats, as was the case with 30 mg/kg of enalapril. The sustained pharmacological effect in rabbits was also confirmed with regard to decreases in effective renal plasma flow and the glomerular filtration rate and increased plasma renin activity. Species differences in the hypotensive effect and mortality could not be explained by toxicokinetic data for the active metabolite of TCV-116 in various species, which supported a possibility that the differences in toxicity may be related 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 rabbits to the pharmacological effects and is caused by marked and sustained hypotension resulting in the decrease in glomerular filtration rate, uremia, and death.
Sato
K
K
Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Takatsuki, Osaka, Japan.
Chatani
F
F
Ito
K
K
Kito
G
G
D000284:Administration, Oral; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D008297:Male; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects*; D012083:Renin / Q000097:blood / Q000187:drug effects; D013045:Species Specificity; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D012083:Renin; C077793:candesartan cilexetil