Marked accumulation of valproic acid in embryonic neuroepithelium of the mouse during early organogenesis.
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.
Dencker
L
L
Department of Toxicology, University of Uppsala, Sweden.
Nau
H
H
D'Argy
R
R
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002490:Central Nervous System / Q000196:embryology / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D005314:Embryonic and Fetal Development / Q000502:physiology; D005229:Fatty Acids, Monounsaturated / Q000493:pharmacokinetics*; D005260:Female; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009436:Neural Tube Defects / Q000139:chemically induced; D011247:Pregnancy
D000927:Anticonvulsants; D002250:Carbon Radioisotopes; D005229:Fatty Acids, Monounsaturated; C014168:2-propyl-2-pentenoic acid