Teratogenicity of valproate conjugates with anticonvulsant activity in mice

Valproic acid (VPA) is an effective antiepileptic medication, the use of which in females of childbearing age is complicated by its ability to induce birth defects, including neural tube defects (NTDs), in exposed embryos. In experimental settings, VPA reproducibly induces NTDs in laboratory animals such as the highly inbred SWV/Fnn mice. In search of new, efficacious derivatives of VPA that lack toxicity, the conjugates of VPA with amantadine (VPA-AMA) and N-3-aminopropyl-2-pyrrolidinone (VPA-PYR) have been synthesized and evaluated for their anticonvulsant activity. In the present study, the authors evaluated the teratogenicity potential of VPA-AMA and VPA-PYR using a well-established mouse model for antiepileptic drug teratogenicity. All tested compounds were injected intraperitoneally to pregnant dams on gestational day 8.5, and the fetuses examined on day 18.5. At the highest dose tested (3.61 mmol/kg), VPA-PYR was maternally lethal, whereas VPA-AMA induced excessive embryonic lethality. At a dose of 2.20 mmol/kg, VPA-PYR was not teratogenic to the exposed embryos; VPA-AMA induced NTDs in 8.2% of embryos, VPA caused 5.5% NTDs. 0.80 mmol/kg amantadine induced NTDs in 2.2% of the exposed fetuses. In conclusion, VPA-AMA has a comparable teratogenicity as does VPA, and it is proposed that the teratogenicity of VPA-AMA is due to the parent compound. Additional studies are needed to fully define and understand the structure-teratogenicity relationships of VPA analogues.