Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: An interspecies comparison

Abstract

This study was undertaken to assess the developmental toxicity and drug distributional and metabolic characteristics of prenatal valproic acid (VPA) exposure in rhesus monkeys. Oral administration of 20-600 mg/kg/day VPA (approximately 1-15 X human therapeutic dose) to 33 animals on variable gestational days (GD) during organogenesis resulted in dose-dependent developmental toxicity manifested as increased embryo/fetal mortality, intrauterine growth retardation, and craniofacial and skeletal defects. Biphasic plasma elimination curves were observed for total and free VPA on the first (GD 21) and last (GD 50) days of treatment in the 100- and 200-mg/kg/day dose groups. VPA exhibited dose-independent elimination kinetics at the plasma concentrations observed in this study. There was no significant change in pharmacokinetic parameters (maternal plasma elimination rate, area under the curve, peak plasma concentration) between the first and last days of treatment at either dose level. Placental transfer studies indicated that embryos were exposed to half the free VPA concentrations present in maternal plasma on GD 37. Comparisons of interspecies sensitivity to VPA-induced developmental toxicity in the mouse, rat, monkey, and man are made.

Teratogenic effects of sodium valproate in mice and rats at midgestation and at term

“…This result shows that plasma peak levels are more relevant than AUC in regard to VPA teratogenesis in this species. Embryo concentration values reported in rats and mice indicate a greater accumulation of VPA in embryonic tissues relative to maternal plasma than observed in monkeys [14,18,19]. On the other hand, the higher embryotoxic effects reported in monkeys in comparison to rats for comparable doses cannot be explained only on the basis of kinetics and placental transport.…”

Antiepileptic Drugs in Pregnancy: Options for the Prevention of Congenital Abnormalities

“…Valproate, and, to a somewhat less extent, carbamazepine, are particularly associated with spina bifida and other neural tube defects, as well as hypospadias [9, 16, 17]. Fetal radial ray defects seem to be an infrequent but rather specific side effect of maternal valproate use, consistent with observations in pregnant Rhesus monkeys [18]. Recently, porencephalic cysts were reported in association with valproate use [19], but this observation awaits confirmation by other studies.…”

Tetramethylcyclopropyl analogue of the leading antiepileptic drug, valproic acid: Evaluation of the teratogenic effects of its amide derivatives in NMRI mice

“…Because other animal species, such as rats and rabbits, are not susceptible to VPA-induced NTDs (Petrere et al, 1986;Menegola et al, 1996), the mice model system is used for the in vivo evaluation of AED-induced NTD potency. Another commonly observed teratogenic effect caused by VPA is skeletal abnormality, which has been detected in many species, including humans, rhesus monkeys, mice, rats, and rabbits (Kao et al, 1981;Ong et al, 1983;Petrere et al, 1986;Vorhees, 1987;Binkerd et al, 1988;Hendrickx et al, 1988). In rodents, the region of the axial skeleton affected by VPA treatment depends on when in the developmental stage the rodent is exposed to VPA (Collins et al, 1991;Menegola et al, 1998).…”