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Modifying Effect of Folinic Acid on Methotrexate‐induced Embryotoxicity in Rats
Author(s) -
HARADA Yasushi,
MISAWA Noriko,
INOMATA Norikazu,
YASUDA Mineo
Publication year - 1986
Publication title -
congenital anomalies
Language(s) - English
Resource type - Journals
eISSN - 1741-4520
pISSN - 0914-3505
DOI - 10.1111/j.1741-4520.1986.tb00682.x
Subject(s) - folinic acid , methotrexate , fetus , gestation , teratology , medicine , pharmacology , endocrinology , chemistry , pregnancy , chemotherapy , fluorouracil , biology , genetics
Embryotoxicity of methotrexate (MTX) and modification of its effect by folinic acid (FA) were evaluated in rats. MTX was administered intraperitoneally to pregnant rats on day 9 of gestation (vaginal plug = day 0), and was followed by an intraperitoneal injection of FA after various time intervals (0‐8 hours). Two dose combinations were used; 0.3 mg/kg of MTX and 1.0 mg/kg of FA, and 3.0 mg/kg of MTX and 10.0 mg/kg of FA. The dams were sacrificed on day 20 of gestation, and the fetuses were examined for visceral and skeletal development. The results are as follows: 1) A single dose of 0.3 mg/kg of MTX resulted in high embryolethality and growth retardation in all live fetuses and a single dose of 3.0 mg/kg of MTX showed 100% embryolethality. 2) A single dose of 1.0 or 10.0 mg/kg of FA showed no embryotoxicity. 3) The mitigating effect of FA on MTX‐induced embryotoxicity was observed when FA was administered simultaneously with MTX, but was rapidly decreased as the time interval between MTX and FA dosings became longer. 4) Some live fetuses which escaped from MTX embryolethality showed growth retardation and dilation of the cerebral ventricles. The dilation of the cerebral ventricles was found even in the simultaneously treated groups, though the incidences were much lower than the belatedly treated groups.