Chronopharmacokinetic Study of Valproic Acid in Man: Comparison of Oral and Rectal Administration

Abstract

Circadian stage-dependent changes of valproic acid (VPA) kinetics was examined after rectal administration comparing after oral dosing. Eight healthy volunteers took a single oral or rectal dose of VPA 400 mg, in a form of sodium valproate, on two occasions, at 8:30 A.M. or 8:30 P.M. Subjects were synchronized with diurnal activity and nocturnal rest as their usual life under standardized meal conditions. After oral administration, mean total VPA concentrations in plasma were significantly higher in the morning than in the evening during the absorption phase. Cmax tended to be higher, tmax was shorter (P less than 0.05) and absorption rate constant (ka) tended to be larger (0.05 less than P less than 0.1) for VPA in the morning than in the evening, although no difference was demonstrated in other pharmacokinetic values between morning and evening trials. After rectal administration, no significant difference was demonstrated in VPA kinetics between morning and evening trials. The rectal administration might have an advantage to eliminate the time-dependent changes of VPA kinetics. Thus the current practice of giving a rectal dose seems to be justified because the time-dependent changes in VPA kinetics observed after oral administration may be reduced without compromising therapeutic efficacy.