Transfer of valproic acid and its main active unsaturated metabolite to the gestational tissue: correlation with neural tube defect formation in the mouse

Abstract

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.