Valproic Acid‐Induced Neural Tube Defects in Mouse and Human: Aspects of Chirality, Alternative Drug Development, Pharmacokinetics and Possible Mechanisms

Abstract

Administration of the antiepileptic drug valproic acid (VPA) during early pregnancy can result in a 1-2% incidence of spina bifida aperta, a closure defect of the posterior neural tube in the human. The predominant defect produced by VPA in the mouse is exencephaly, a closure defect of the anterior neural tube. Recent experiments demonstrate that an appropriate dosing regimen (consecutive doses of VPA on day 9 of gestation) can also result in a low incidence of spina bifida aperta, and a high incidence of spina bifida occulta in the mouse as a potential animal model. Relatively high doses and concentrations of VPA are needed in the mouse to produce neural tube defects, the human appears to be more sensitive in this regard. Maximal concentrations and not AUC (area under the concentration-time curve) values correlate with the incidence of neural tube defects in the mouse which could in part be explained by saturation of plasma protein binding, increased free drug available for placental transfer and the embryonic neuroepithelium acting as a "deep compartment". It is likely that the parent drug and not a metabolite is the proximate teratogen. Structure-activity relationships show a strict structural requirement for high teratogenic potency: the molecule must contain an alpha-hydrogen atom, a carboxyl function, branching on carbon atom 2 with two chains containing 3 carbon atoms each for maximum activity. If these two carbon chains are different, then enantiomers are present such as the R- and S-enantiomers of 2-n-propyl-4-pentenoic acid (4-en-VPA), 2-n-propyl-4-pentynoic acid (4-yn-VPA) and 2-ethylhexanoic acid. These enantiomers were synthesized and shown to be significantly different in regard to teratogenic potency. Pharmacokinetic studies indicate that both enantiomers of each compound reach the embryo to the same degree. Therefore, the intrinsic teratogenic activity of the enantiomers differ, suggesting a stereoselective interaction between the drugs and a chiral structure within the embryo, is involved in the mechanism of action. In sharp contrast to the teratogenic effect, the anticonvulsant activity and neurotoxicity of this compound class show broad structural specificity, opening the possibility for development of novel antiepileptic agents with low teratogenic potency such as 2-n-propyl-2-pentenoic acid (2-en-VPA). The molecular mechanism of the teratogenicity of VPA is quite unknown; of the several hypothesis suggested, the interaction of VPA with embryonic folate metabolism is discussed here.

Valproic Acid: Second Generation

“…6,7,14 Structure-activity relationship studies conducted in mice strains prone to VPA-associated teratogenicity indicate that to be teratogenic, and to cause neural tube defects in mice embryos, VPA analogues and derivatives should contain a tertiary carbon bound to a carboxylic group, a hydrogen atom, and two alkyl chains. [14][15][16] A VPA derivative lacking any one of these structural requirements has the potential to become a nonteratogenic entity. 6,7,[14][15][16] For example, the corresponding CNS-active amide of VPA valpromide (VPD) that has a carboxamide moiety instead of a carboxylic group is not teratogenic.…”

“…[14][15][16] A VPA derivative lacking any one of these structural requirements has the potential to become a nonteratogenic entity. 6,7,[14][15][16] For example, the corresponding CNS-active amide of VPA valpromide (VPD) that has a carboxamide moiety instead of a carboxylic group is not teratogenic. 17 Similarly, the active metabolite of VPA is 2-ene-VPA, which does not have an ␣-hydrogen to the carboxylic moiety, is also nonteratogenic.…”

Mood stabilizer psychopharmacology

“…Some studies suggest that valpromide (similar to VPA, but the carboxyl group is modified to an amide) also has antimanic properties [206]. Valpromide does not inhibit HDAC, does not result in neural tube defects in mouse embryos or the loss of anterior structures that characterizes Xenopus embryos following VPA injection, but does protect against chemically induced seizures in mice [140,[220][221][222][223][224]. Furthermore while the two stereoisomers of VPA have identical antiepileptic properties, only one stereoisomer is teratogenic [224].…”

Anticonvulsant Profile and Teratogenicity of N‐methyl‐tetramethylcyclopropyl Carboxamide: A New Antiepileptic Drug

“…1), the primary amide of VPA, is 4 to 10 times more potent than VPA as an AED in rodents and does not appear to induce NTDs in animal models (7). However, the better anticonvulsant potency of VPD, when compared with VPA, and the lack of teratogenicity have little clinical applicability in humans because in humans, VPD acts as a prodrug and is rapidly biotransformed to VPA (8).…”

“…The evidence to date would suggest that VPA itself, and not one of its known metabolites, is the teratogenic agent (6). Structure-activity relationship studies of VPA derivatives and its analogues have demonstrated that three structural requirements are associated with VPA analogues that induce NTDs: (a) a free carboxyl group; (b) a hydrogen atom in an ␣-position to the carboxyl; and (c) branching on carbon atom two with two alkane chains containing three carbon atoms (7).…”