Bidirectional interaction of valproate and lamotrigine in healthy subjects

Clin Pharmacol Ther. 1996 Aug;60(2):145-56. doi: 10.1016/S0009-9236(96)90130-7.


Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / adverse effects
  • Anticonvulsants / pharmacokinetics*
  • Anticonvulsants / pharmacology
  • Drug Administration Schedule
  • Drug Interactions
  • Half-Life
  • Humans
  • Lamotrigine
  • Male
  • Reference Values
  • Time Factors
  • Triazines / administration & dosage
  • Triazines / adverse effects
  • Triazines / pharmacokinetics*
  • Triazines / pharmacology
  • Valproic Acid / administration & dosage
  • Valproic Acid / adverse effects
  • Valproic Acid / pharmacokinetics*
  • Valproic Acid / pharmacology


  • Anticonvulsants
  • Triazines
  • Valproic Acid
  • Lamotrigine