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Toxicology. 1975;4(1):65-73.

Effects of amethopterin (methotrexate) on the evolution of pregnancy in rats.


Amethopterin (4-amino-N-10-methyl-glutamic acid) was given to pregnant rats in varying doses at different periods of gestation to evaluate its effects upon both the mother and the fetoplacental unit. The maternal organism is more sensitive to this drug at days 14 to 17 than at a larger stage of gestation. When administered to rats from day 14 to day 18 of pregnancy the drug is capable of inducing a series of deleterious effects: maternal weight loss, resorption, abortion or hypotrophy of fetuses. Day 16 appears to be a critical moment in the evolution of rat pregnancy, after which injection of amethopterin does no longer impair fetoplacental growth. Before this date, the drug directly inhibits fetal weight gain, whereas the sensitivity of the placenta is only transient at day 16 resulting in maximum weight decrease of this organ 24 h later. Its action on rat pregnancy follows a direct dose-effect relationship reflecting increasing damage to the products of conception (resorption, abortion and hypotrophy).


Varying doses of amethopterin were injected intraperitoneally into S prague-Dawley and Wistar rats at different periods of gestation to evalu ate the effects on rat pregnancy and fetal outcome. Anorexia, diarrhea and vaginal bleeding were observed with repeated doses of more than .5 mg/kg. When administered for 5 consecutive days, a weight loss of up to 49.93 gm was observed. 5 daily doses of 1.5 mg/kg or more resulted in a 100% death rate of Sprague-Dawley rats. Abortions were common in Wistar rats given a dose higher than .5 mg/kg. A 100% resorption rate was observed in Wistern rats given 2.0 mg/kg for 5 days. Hypotrophic fetuses were observed in both strains when .5 mg/kg was administered for 5 days. Fetal growth rate was significantly lower from day 14 to day 17 of drug treatment, whcih seemed to be the time when the animals are most sensitive to the drug. The effects of amethopterin before day 17 follow a direct dose-effect relationship.

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