Effect of Valproate Dose on Formation of Hepatotoxic Metabolites

Valproate (VPA) therapy has been associated with a rare but fatal hepatotoxicity. 4-ene-VPA and 2(E),4-diene-VPA, unsaturated metabolites of VPA, are hepatotoxins several times more potent than VPA. In a previous study, a dose-dependent excretion of hepatotoxic metabolites was noted in patients receiving VPA. Our study was designed to evaluate the effect of dose on VPA metabolism under controlled conditions. Nineteen healthy volunteers sequentially received three different daily doses of VPA (250, 500, and 1,000 mg). Each dose was given twice daily for 4 days. Urine was collected for one dosage interval (12 h) at steady state for each dose and assayed for 15 VPA metabolites by gas chromatography/mass spectrometry (GCMS). Blood samples were also obtained from eight of the subjects, and VPA was assayed by GCMS. No effect of dose was noted on total plasma clearance. There was a significant dose-dependent decrease in intrinsic hepatic clearance. The intrinsic formation clearance (Cl(f)) of the 4-ene-VPA pathway showed a statistically significant dose-dependent increase (0.22, 0.33, 0.40 ml/h/kg). The corresponding percentage of dose recovered as 4-ene-VPA and its sequential metabolites showed significant dose-dependent increases (0. 15, 0.27, 0.62%). The role of VPA dose in the pathogenesis of hepatotoxicity may be more important than was previously believed.