Chronopharmacokinetics of valproic acid following constant-rate administration in mice and influence of feeding schedule

Aim: To study the circadian rhythm in pharmacokinetics of valproic acid (VA) and influence of feeding schedule on the rhythm. Methods: Sodium valproate was administered by osmotic minipump technique (1.062 mg · h^-1) and iv (50 mg · kg^-1) to ICR mice fed under ad lib or time-restricted schedules to determine the time-dependent changes of VA kinetics. Results: Plasma VA concentration and clearance at steady-state showed circadian rhythms (P < 0.01). Time-restricted feeding influenced the rhythm of VA kinetics, acrophases of rhythms shifted approximately 12 h. Conclusion: Timing of dosing is important for VA kinetics and feeding schedule is one of synchronizers in VA kinetics.