ETHANOL POTENTIATES VALPROIC ACID-INDUCED NEURAL-TUBE DEFECTS (NTDS) IN MICE DUE TO TOXICOKINETIC INTERACTIONS

Both the antiepileptic drug valproic acid (VPA) and ethanol interfere with fetal folate metabolism, which may contribute to their mechanism of teratogenesis. Therefore, the possible interaction between VPA and ethanol was investigated in mice. Ethanol (2 x 2.5 g/kg) was given ora lly 4 and 1 h prior to VPA (300 and 400 mg/kg, SC) in day 8.25 pregnan t NMRI mice, Fetuses were examined for exencephaly, embryolethality, a nd fetal weight retardation on day 18 of gestation. Higher doses of et hanol (2 x 5 g/kg, orally) at day 7.5 and 8 of gestation resulted in 2 2% embryolethality and 1,7% exencephaly with no effect on fetal weight . Ethanol, however, increased VPA (400 mg/kg, SC)-induced exencephaly, embryolethality, and fetal weight retardation, It also increased VPA (300 mg/kg, SC)-induced exencephaly without affecting embryotoxicity. A minimum of two oral doses of 2.5 g/kg ethanol, 1 and 4 h, or 1 and 6 h prior to VPA administration were needed to produce maximum potentia tion of the effects observed. These ethanol doses increased plasma VPA levels of day 8.25 pregnant mice given 400 mg/kg VPA to values compar able to the levels of mice given only VPA at a higher dose level (500 mg/kg). The incidence of exencephaly was increased from 35% for VPA (4 00 mg/kg) to 59% when VPA was given with ethanol. This incidence was s imilar to that of 60% for the high dose of VPA (500 mg/kg) administere d without ethanol. Maternal plasma ethanol concentration peaked at 193 , 196, and 183 mg/dL 15, 30, and 60 min, respectively, after oral etha nol administration (2.5 g/kg), and fell to 110 mg/dL by 2 h. Animals w ere slightly sedated 0.25 to 1 h after ethanol administration. These r esults indicate that potentiation of VPA-induced teratogenesis by etha nol is related to decreased VPA elimination, but do not exclude potent iation of VPA-induced interference with folate metabolism, which remai ns to be verified.