Altered Pharmacokinetics and Metabolism of Valproate after Replacement of Conventional Valproate with the Slow‐Release Formulation in Epileptic Patients

Abstract

Altered metabolism of valproate has been suggested as the mechanism of teratogenicity and hepatotoxicity of valproate. This study aimed at examining whether pharmacokinetics of a slow-release formulation of valproate affects valproate metabolism. Thirty-one epileptic patients were treated with fixed-doses of conventional valproate for at least 2 months. Thereafter, the drug was replaced with the same doses of slow-release formulation of valproate for 2 months. Blood samplings for determination of valproate and its metabolites by gas chromatography-mass spectrometry were performed at three time-points (just before morning dose and at 1 and 5 hr after morning dose) during both treatment phases. There was a significant difference (P < 0.005) in the mean serum concentration (+/- S.D.) of valproate after 1 hr between conventional valproate (63.1 +/- 27.9 microg/ml) and slow-release formulation of valproate (45.7 +/- 19.5 microg/ml). Mean serum concentrations (+/- S.D.) of 4-en and hydroxy metabolites after 5 hr were significantly reduced after replacement with slow-release formulation of valproate (4-en: 29.5 +/- 14.0-->23.0 +/- 15.3 ng/ml, 3-OH: 488.5 +/- 234.0-->419.6 +/- 171.1 ng/ml, 4-OH: 404.3 +/- 124.7-->342.8 +/- 147.6 ng/ml, 5-OH: 102.8 +/- 54.4-->81.0 +/- 43.6 ng/ml). The present study suggests that smaller diurnal fluctuations in valproate concentrations during treatment with slow-release formulation of valproate result in decreased formations of minor metabolites including 4-en, the most toxic metabolite.