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


  • M. M. A. Elmazar,

    1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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  • Dr. H. Nau

    Corresponding author
    1. Institute of Toxicology and Embryopharmacology, Free University, Berlin, Germany
    • Institute of Toxicology and Embryopharmacology, Free University, Garystrasse 5, D-1000 Berlin 33, Germany
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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.