Abstract
The diurnal variation in pharmacokinetics of valproic acid (VPA) was studied at unequal dosing intervals, because patients generally take drugs with each meal or with poor compliance. Six healthy volunteers (22 to 32 years old) orally took 300 mg of sodium valproate at 9 : 00 and 18 : 00 each day for 6 d. On the sixth day, blood was drawn periodically for 24 h for pharmacokinetic analysis. Faster absorption and a shorter absorption lag-time were observed at morning dosing after a light meal, and this may be meal-related. The systemic clearance and the mean plasma level during day were in good agreement with those during the night, although VPA plasma levels showed large diurnal fluctuations. Plasma albumin concentration at night was significantly decreased and this seems consistent with the finding that the free fraction (FF) of VPA was higher during the night. A significant negative correlation between plasma albumin concentration and the FF was observed. These results suggest that the VPA dosing schedule used here is adequate for maintaining the mean plasma level in an appropriate range. Mealtimes and blood sampling times should the taken into account in routine plasma VPA level monitoring to minimize the influence of diurnal variation.
