Altered pharmacokinetics and metabolism of valproate after replacement of conventional valproate with the slow-release formulation in epileptic patients.

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.