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Sowohl klinische als auch vor allem experimentelle Studien lassen den Schlus zu, das VPA teratogene Effekte induzieren kann. Mus diese Substanz wahrend der Schwangerschaft verabreicht werden, soll die Dosis moglichst gering gehalten und auf mehrere tagliche Gaben pro Tag aufgeteilt werden. Experimentelle Studien zeigen eine hohe Strukturspezifitat des teratogenen Effekts, so das moglich erscheint, antiepileptisch wirksame Substanzen mit niedriger teratogener Potenz wie das 2–en-VPA zu entwickeln. Der Mechanismus des teratogenen Effekts ist noch unbekannt, eine Beeinflussung des Folatstoffwechsels ist wahrscheinlich.

It becomes increasingly clear that the dose is often an unsatisfactory correlate to the toxic effect produced by a drug or environmental agent. The effect in a particular target organ is strictly dependent on the concentration-time relationships of the drug and/or its active metabolite(s) in the target tissue, reactive metabolites formed or specific binding phenomena (Monro, 1992). Thus, an effect is dependent on the chemical structure of the xenobiotic (intrinsic activity), the exposure of the target tissue, and the susceptibility or sensitivity toward a particular insult (pharmacogenetics). This general concept will be discussed here with regard to drug teratogenesis, where it is particularly helpful to explain and overcome species differences, which are so extreme in this area of toxicology.

A single dose of 500 mg thiamphenicol (TAP) was given to 30 women at various times prior to interruption of pregnancy for social and/or medical reasons during the first trimester (curettage, hysterotomy, or prostaglandin induction). Concentrations of TAP were then determined in maternal serum, placental, and fetal tissues by a gas chromatographic method using electron capture detection. Similar, but sometimes significantly higher, concentrations of TAP were found in placental and fetal tissues as compared to maternal serum (data expressed as μg/ml or μg/g).

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; Jager-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 (Jager-Roman et al. 1986).