Teratogenicity of Valproic Acid and Related Substances in the Mouse: Drug Accumulation and pH_i in the Embryo During Organogenesis and Structure-Activity Considerations

Abstract

The antiepileptic drug valproic acid is a putative human teratogen as suggested by retrospective studies (Robert and Rosa 1983; Lindhout and Meinardi 1984), a number of case reports (reviewed in Tein and McGregor 1985) and prospective investigations (Koch et al. 1983; Jäger-Roman et al. 1986; Nau et al. 1981a). The use of thus drug for seizure control during pregnancy was shown to result in an increased incidence of neural tube defects, in particular spina bifida aperta in addition to numerous other malformations, particularly of the face and the skeletal structures. Clinical doses range between 10–40 mg/kg/day administered as a single daily dose (Rowan et al. 1981) or in divided doses (Gjerloff et al. 1984). The therapeutic range is said to be between 50–100 µg/ml, although peak drug levels may be much higher: Rowan et al. (1981) reported peak levels of 180 µg/ml in a patient treated with a once-a-day dosing regimen. We have recently measured peak levels of 120 and 184µg/ml in two epileptic patients during the first trimester of pregnancy (Jäger-Roman et al. 1986).