Circadian changes of valproate kinetics depending on meal condition in humans

The objective of this study was to examine the effect of meal condition on circadian changes in valproic acid (VPA) kinetics. Two experiments were performed in 16 healthy men that were synchronized with diurnal activity and nocturnal rest as their routine life. In both experiments, four 200-mg tablets of VPA were given orally on two occasions in the morning (8:30 AM) or in the evening (8:30 PM). In each study, a randomized, single-dose, two-way crossover design was used, and 2 weeks elapsed between morning and evening trials. In experiment 1, eight subjects took a light meal as breakfast between 8:00 and 8:15 AM and a heavy meal as dinner between 6:00 and 6:30 PM to fit the subject's usual food amount. The mean peak plasma concentration (Cmax) was significantly higher (P less than .01), the time to peak concentration (tmax) was shorter (P less than .05), and the absorption rate (Ka) was larger (P less than .05) after the morning dose than after the evening dose. In experiment 2, the size and contents of meal in breakfast and dinner were prepared in the same manner as the standard breakfast for the subjects. Namely, eight subjects took the same light meal between 8:00 and 8:15 AM in the morning and between 8:00 and 8:15 PM in the evening. There was no significant circadian change in VPA kinetics under this same meal condition. These results suggest that the differences of meal condition between morning and evening in our daily life play a major role in the mechanism underlying the circadian changes of VPA absorption in man.