Methotrexate increases valproic acid‐induced developmental toxicity, in particular neural tube defects in mice

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The hypothesis that valproic acid‐induced dysmorphogenesis may be due to an interference of this drug with folate metabolic pathways was further investigated by a study of a possible interaction of valproic acid (VPA) and the established folate antagonist methotrexate (MTX). The dihydrofolate reductase inhibitor MTX (1.25 and 2.5 mg/kg, i. p.) was injected 15 min prior to VPA (300 and 400 mg/kg, s. c.) in day 8 pregnant NMRI mice. Fetuses were examined for exencephaly, resorption, and fetal weight retardation on day 18 of gestation. MTX produced no exencephaly or reduction in fetal weight, and the 2.5‐mg/kg dose caused 56% resorption. Higher doses (5–20 mg/kg) produced embryolethality and fetal weight retardation, but no exencephaly. VPA (300 and 400 mg/kg) administration resulted in 3.4% and 12.6% exencephaly and 9% and 19% resorptions, respectively. Coadministration of MTX with VPA significantly increased VPA‐induced resorption and exencephaly rates as well as fetal weight retardation. Exencephaly induced by VPA 400 mg/kg was increased to 29.5% and 24.1% (P < 0.01 and P < 0.05) when given with 1.25 and 2.5 mg/kg MTX, respectively. MTX (2.5 mg/kg i.p.) did not alter transplacental VPA (400 mg/kg, s.c.) pharmacokinetics. These results support the view that VPA‐induced teratogenesis may be mediated by interaction with folate metabolism. © 1992 Wiley‐Liss, Inc. Copyright © 1992 Wiley‐Liss, Inc., A Wiley Company

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