Effects of valproic acid, some of its metabolites and analogues on prenatal development of rats in vitro and comparison with effects in vivo

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Abstract
Using a whole-embryo culture system valproic acid (VPA) and some of its metabolites (2-en-VPA, 4-en-VPA, 4,4′-dien-VPA) and analogues (ethyl-propyl-acetic acid, propyl-butyl-acetic acid, di-butyl-acetic acid, 2-methyl-2-ethyl-hexanoic acid, 1-methyl-1-cyclohexanoic acid) were tested for their potential to induce abnormal development. With regard to embryonic growth, development and abnormality rate, the tested compounds showed a wide range of “teratogenic potency” in vitro. In order to verify some of the in vitro results, in vivo experiments were performed. Pregnant rats were treated subcutaneously on day 10 of gestation with 2×330 mg VPA/kg, or 2×400 mg 2-en-VPA/kg, respectively. Evaluation of the embryos was performed on day 11.5 of gestation, corresponding to the in vitro experiments. VPA showed a high potential to induce abnormal development in vivo as well as in vitro, whereas 2-en-VPA was inactive under our experimental conditions. Problems connected with the evaluation of the predictive value of an in vitro test system for the detection of embryotoxic effects, such as “validation” and significance of pharmacokinetic data, are discussed.