Pharmacokinetics of Valproic Acid and Its Metabolites after a Single Oral Administration of a Sustained-Release Preparation of Sodium Valproate(KW-6066 N)

Abstract

The kinetics and metabolic disposition of valproic acid following a single oral administration of two preparations of sodium valproate (sustained-release tablets, KW-6066 N ;and standard tablets, Depakene) were investigated by a Latin square cross-over method insix subjects. Determination of valproic acid and its metabolites in the serum and urinewas performed by GC/MS method.
The mean elimination constants (k_e), apparent volumes of distribution (V_d), areas underthe serum concentration-time curve (AUC) of the parent drug, and the sum of valproicacid and its metabolites excreted in urine showed no significant differences in the twopreparations. Therefore the extent of bioavailability of Depakene and KW-6066 N seemedto be equivalent.
The pharmacokinetic parameters were estimated according to one-compartment openmodel by simultaneous least squares curve fitting method. KW-6066 N exhibited a moreprolonged absorption of valproic acid, showed a more delayed peak time (t_max), and yieldeda longer mean residence time (MRT). Maximum serum concentration (C_max) obtained afteradministration of KW-6066 N was lower than those following the standard tablets of Depakene. These results indicate that KW-6066 N provides slow release of valproic acid.
Using the pharmacokinetic parameters of valproic acid obtained in the study, serumconcentrations of valproic acid after repeated oral administration of Depakene or KW-6066N were simulated. KW-6066 N was expected to be effective even when administeredonce a day.