Evaluation of the reproductive and developmental toxicity of the AT1-selective angiotensin II receptor antagonist losartan in rats.
Losartan, an AT1-selective angiotensin II receptor antagonist, was evaluated in female rats for effects on fertility, reproduction, and perinatal and postnatal development. In a range-finding study, pregnant rats were treated orally from gestation days 6-17 (GD 6-17) with doses of 25, 75, 150, 225, and 300 mg Losartan/kg/day. There were treatment-related decreases in maternal body weight gain, slight treatment-related decreases in hemoglobin concentration, and slight treatment-related increases in serum urea nitrogen in the 225 and 300 mg/kg/day groups. In a fertility study, female rats were treated for 15 days prior to mating, during mating, and GD 0-19 with doses of 25, 100, and 300 mg Losartan/kg/day. The initial dose of 300 mg/kg/day was lowered to 200 mg/kg/day at the start of mating due to excessive body weight loss during the premating treatment interval. There were no treatment-related effects on reproductive performance, mating, or fertility indices in the F0 generation. There was no evidence of treatment-related or dose-related fetal malformations. However, decreased F1 pup body weights were observed in all drug-treated groups. In the 100 and 300/200 mg/kg/day groups there were treatment-related increases in F1 pup mortality and alterations in the pattern of postweaning body weight gains. There was also a delay in developmental signs in the 100 and 300/200 mg/kg/day groups, which were likely secondary to the decreased weight of the pups in these groups. In a developmental toxicity study, pregnant rats were administered 50, 100, and 200 mg Losartan/kg/day on GD 6-17. There was no evidence of developmental toxicity in any dose group. Maternal toxicity was evident in the 200 mg/kg/day group as a treatment-related decrease in body weight gain during gestation. In a late-gestation/lactation study, pregnant rats were administered 10, 25, and 100 mg Losartan/kg/day on GD 15 through lactation day 20 (LD 20). There were treatment-related decreases in maternal body weight gain during gestation and lactation in the 100 mg/kg/day group. Decreased pup weights were noted in all dose groups, and pre- and postweaning pup deaths were observed in the high dose group which were comparable to those observed in the female fertility study. The lack of fetal body weight effects at 100 mg Losartan/kg/day in the developmental toxicity study, with treatment ending on GD 17, indicates that adverse effects observed in the F1 generation in the fertility and late-gestation/lactation studies were due to exposure during late gestation and/or lactation.(ABSTRACT TRUNCATED AT 400 WORDS)
Spence
S G
SG
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Cukierski
M A
MA
Manson
J M
JM
Robertson
R T
RT
Eydelloth
R S
RS
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity*; D001713:Biphenyl Compounds / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007093:Imidazoles / Q000633:toxicity*; D007774:Lactation; D019808:Losartan; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*; D013777:Tetrazoles / Q000633:toxicity*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013723:Teratogens; D013777:Tetrazoles; D019808:Losartan