Chronopharmacoiogical Study of Sodium Valproate in Mice: Dose-Concentration-Response Relationship

Effects of the time-of-day of drug administration on the pharmacokinetics electroshock seizure (ES) threshold and acute toxicity were investigated in mice with sodium valproate (VPA). ICR male mice, housed under a light-dark (12:12) cycle, were orally administered 600 mg/kg VPA for anticonvulsant effect studies and administered 1 500 mg/kg VPA for acute toxicity studies. A significant circadian rhythm was demonstrated for the ES threshold at 30 mm after VPA administration, with the highest value in the light phase and the lowest in the dark phase, although no rhythm was shown in the nondrugged state. A significant circadian rhythm was also shown for plasma and brain VPA concentrations. This finding nicely corresponded to the circadian rhythm in the ES threshold. The positive relationship between the brain VPA concentration and the ES threshold was not different between the light phase and the dark phase. There was also a significant circadian rhythm in the acute toxicity induced by VPA, with the highest mortality in the light phase and the lowest in the dark phase. The results suggest the importance of time in the circadian stage at which VPA is administered in the experimental studies in mice and the significance of circadian rhythm in VPA kinetics in relation to the rhythm of ES threshold.