Bidirectional interaction of valproate and lamotrigine in healthy subjects.

Journal Article (Clinical Trial;Journal Article)


To evaluate the steady-state pharmacokinetics of lamotrigine and valproate at three dosing levels of lamotrigine in normal volunteers receiving steady-state therapeutic doses of valproate.


This was an open-label, randomized, three-way crossover study of 18 normal male volunteers. Subjects received oral valproate (500 mg Depakote twice a day) throughout the study. Each subject subsequently received three oral dosage regimens of lamotrigine (50, 100, or 150 mg/day) for 1 week each, with a 2-week washout period between lamotrigine treatment periods. Valproate and lamotrigine trough plasma samples were determined by a capillary gas chromatography method and immunofluorometric assay, respectively. Urine samples were assayed for 11 valproate metabolites by gas chromatography/mass spectrometry.


When compared to other studies in which lamotrigine was administered with no concurrent antiepileptic drug, concomitant valproate markedly increased the half-life of lamotrigine and decreased lamotrigine clearance, without substantial alteration in the linear kinetics of the drug. The addition of lamotrigine was associated with a small but significant 25% decrease in steady-state valproate plasma concentration. Oral clearance of valproate was increased (from 7.2 +/- 1.1 ml/hr/kg before lamotrigine treatment to 9.0 +/- 2.0 ml/hr/kg on day 28; p < 0.05). The formation clearance of the hepatotoxic valproate metabolites, 2-n-propyl-4-pentenoic acid (4-ene-valproate) and 2-propyl-2,4-pentadienoic acid [2(E),4-diene-valproate], was unaffected by lamotrigine administration.


As a consequence of the interaction between lamotrigine and sodium valproate, a dosage reduction of lamotrigine should be considered in patients taking a combination of valproate and lamotrigine.

Full Text

Duke Authors

Cited Authors

  • Anderson, GD; Yau, MK; Gidal, BE; Harris, SJ; Levy, RH; Lai, AA; Wolf, KB; Wargin, WA; Dren, AT

Published Date

  • August 1996

Published In

Volume / Issue

  • 60 / 2

Start / End Page

  • 145 - 156

PubMed ID

  • 8823232

Electronic International Standard Serial Number (EISSN)

  • 1532-6535

International Standard Serial Number (ISSN)

  • 0009-9236

Digital Object Identifier (DOI)

  • 10.1016/s0009-9236(96)90130-7


  • eng