CHRONOTOXICITY OF SODIUM VALPROATE IN PREGNANT MOUSE AND EMBRYO

The influence of dosing time on the embryotoxicity of sodium valproate (valproic acid, VPA) was investigated in ICR mice under a light-dark (12: 12) cycle. A significant circadian rhythm was shown for VPA-induc ed embryotoxicity, with the highest value at 1700 and the lowest at 01 00. A similar pattern of rhythm was also shown for VPA-induced toxicit y in pregnant and nonpregnant mice. No significant dosing time-depende nt difference between injection at 1700 and 0100 was demonstrated for VPA concentrations in the embryo, plasma and brain. The rhythm in the embryotoxicity seems to be related to the rhythm in the sensitivity of the embryo and dam to the drug. Embryotoxicity and VPA concentrations were significantly higher on gestational day 13 than day 7. The pharm acokinetics of VPA contribute, at least partly, to the gestational sta ge-dependent embryotoxicity of VPA. The timing of drug administration (i.e., gestational stage and circadian phase) appears to be essential for studies on the embryotoxicity of VPA in mice.