Methotrexate increases valproic acid‐induced developmental toxicity, in particular neural tube defects in mice
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
Elmazar, Mohamed M. and Nau, H., "Methotrexate increases valproic acid‐induced developmental toxicity, in particular neural tube defects in mice" (1992). Pharmacy. 259.