trans-2-en-valproate and Neural-Tube-Defects

Valproic acid, an antiepileptic drug, causes neural tube defects in mice and man. 14C-labeled valproic acid (sodium-salt) was administered to pregnant mice on days 8 and 9 of gestation (period of high sensitivity in regard to formation of neural tube defects in this species). Two dose levels of valproic acid (1 and 400 mg/kg) were used; in each case the total radioactivity administered was the same: 400 microCi/kg or 14.7 MBq/kg. Autoradiography combined with computerized densitometry revealed that in low-dose animals most of the radioactivity was confined to maternal liver and kidney, while at high doses more activity was observed in soft tissues and fluids, including amniotic fluid. In the embryo, the neuroepithelium showed the highest concentration, irrespective of dose and survival interval (30 min, 3 h, and 6 h). Upon administration of the high dose, up to five times more radioactivity (approximately 2,000 times more valproic acid) was recovered in embryonic tissues than after the low dose. It is concluded that high doses of VPA saturate the capacities of metabolism, excretion, and protein binding in the maternal organism, resulting in a higher proportion of the dose reaching the embryo, allowing more of the drug to be accumulated by the target organ, the neuroepithelium.

Topics: Animals; Anticonvulsants; Carbon Radioisotopes; Central Nervous System; Embryo, Mammalian; Embryonic and Fetal Development; Fatty Acids, Monounsaturated; Female; Kidney; Liver; Mice; Mice, Inbred Strains; Neural Tube Defects; Pregnancy

The pharmacokinetics of the antiepileptic drug valproic acid (2-propyl-pentanoic acid; VPA) and its main active metabolite 2-en-VPA (2-propyl-2-pentenoic acid) in mouse serum and gestational material were studied and correlated with the drastic differences between the two compounds in their embryotoxicity. The peak levels of VPA reached after 0.5 hours were only slightly higher than that of 2-en-VPA (both in mother and gestational material). The free concentrations of VPA and 2-en-VPA in maternal serum also peaked at 0.5 hours. After that time the free maternal serum levels of 2-en-VPA decreased much more rapidly than the concentrations in the gestational materials. The area under the concentration/time curves (AUC) values of 2-en-VPA in mother and embryo were lower than corresponding values of VPA; the higher clearance of 2-en-VPA was predominantly due to an increased volume of distribution. Since we have previously shown that the peak concentrations and not the AUC values of VPA correlated with the teratogenicity of this compound, our present data indicate that the low teratogenic and embryotoxic potential of 2-en-VPA is a result of the intrinsic activity of this compound and not of lower peak concentrations reached in mother and embryo.

Topics: Administration, Oral; Animals; Anticonvulsants; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Gestational Age; Injections, Intraperitoneal; Injections, Subcutaneous; Kinetics; Maternal-Fetal Exchange; Mice; Neural Tube Defects; Pregnancy; Valproic Acid