Formulations of Valproate Alter Valproate Metabolism: A Single Oral Dose Kinetic Study

Abstract

The risk for teratogenicity of valproate (VPA) increases in a dose- or concentration-dependent manner. It has been also suggested that an increased metabolic conversion of VPA to its toxic metabolites including 2-propyl-4-pentenoic acid (4-en) is involved in the mechanism of VPA toxicity at higher doses and concentrations. This study aimed to examine whether formulations of VPA alter metabolism of VPA itself. Seven healthy male volunteers received an oral dose (800 mg) of conventional and slow-release formulations of VPA on 2 separate days, consisting of 2 phases of single-dose kinetic trials. Blood sampling for determination of VPA and its monounsaturated (2-en, 3-en, and 4-en) and hydroxylated (3-OH, 4-OH, and 5-OH) metabolites by gas chromatography-mass spectrometry were performed up to 60 hours after dosing. In subjects receiving the slow-release formulation of VPA, decreased Cmax, prolonged Tmax, and reduced area under the curve of metabolites by microsomal oxidation (4-en, 4-OH, and 5-OH) were observed. In contrast, aforementioned kinetic parameters of beta-oxidative metabolites (2-en, 3-en, and 3-OH) were unchanged irrespective of VPA formulations. These results suggest that the slow-release formulation may be safer with regard to pharmacokinetic and metabolic aspects, which is characterized by decreased formation of 4-en, the most toxic metabolite, together with reduced peak concentrations of the parent compound.