Neurochemical Research

, Volume 41, Issue 5, pp 1185–1191 | Cite as

Mexiletine and its Interactions with Classical Antiepileptic Drugs: An Isobolographic Analysis

  • Kinga K. Borowicz-Reutt
  • Monika Banach
  • Barbara Piskorska
Original Paper


Using the mouse maximal electroshock test, the reference model of tonic–clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23 % the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations.


Mexiletine Antiepileptic drugs Maximal electroshock Drug interactions Isobolographic analysis 



This study was made possible by a Grant (DS 473/15) from the Medical University of Lublin, Poland.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Wang Y, Mi J, Lu K, Lu Y, Wang K (2015) Comparison of gating properties and use- dependent block of Nav1.5 and Nav1.7 channels by anti-arrhythmics mexiletine and lidocaine. PLoS One. doi: 10.1371/journal.pone.0128653
  2. 2.
    Alexander GJ, Kopeloff LM, Alexander RB, Chatterjie N (1986) Mexiletine: biphasic action on convulsive seizures in rodents. Neurobehav Toxicol Teratol 8:231–235PubMedGoogle Scholar
  3. 3.
    Williams AJ, Tortella FC (2002) Neuroprotective effects of the sodium channel blocker RS100642 and attenuation of ischemia-induced brain seizures in the rat. Brain Res 932:45–55CrossRefPubMedGoogle Scholar
  4. 4.
    Enoki H, Hata H, Ohmori I, Maniwa S, Ohta H, Kobayashi K (2000) Clinical applications and the effect of mexiletine on refractory epilepsies. No To Hattatsu 32:29–34PubMedGoogle Scholar
  5. 5.
    Miyamoto A, Takahashi S, Oki J (1999) A successful treatment with intravenous lidocaine followed by oral mexiletine in a patient with Lennox-Gastaut syndrome. No To Hattatsu 31:459–464PubMedGoogle Scholar
  6. 6.
    Nakazawa M, Okumura A, Niijima S, Yamashita S, Shimono K, Hirose S, Shimizu T (2013) Oral mexiletine for lidocaine-responsive neonatal epilepsy. Brain Dev 35:667–669CrossRefPubMedGoogle Scholar
  7. 7.
    Castel-Branco MM, Alves GL, Figueiredo IV, Falcão AC, Caramona MM (2009) The maximal electroshock seizure (MES) model in the preclinical assessment of potential new antiepileptic drug. Methods Find Exp Clin Pharmacol 31:101–106CrossRefPubMedGoogle Scholar
  8. 8.
    Borowicz KK, Banach M, Zarczuk R, Łukasik D, Łuszczki JJ, Czuczwar SJ (2007) Acute and chronic treatment with mianserin differentially affects the anticonvulsant activity of conventional antiepileptic drugs in the mouse maximal electroshock model. Psychopharmacology 195:167–174CrossRefPubMedGoogle Scholar
  9. 9.
    Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–113PubMedGoogle Scholar
  10. 10.
    Boissier JR, Tardy J, Diverres JC (1960) Une nouvelle methode simple pour explorer l’action tranquilisante: le test de la cheminee. Med Exp (Basel) 3:81–84CrossRefGoogle Scholar
  11. 11.
    Tallarida RJ (2000) Drug synergism and dose-effect data analysis. Chapton & Hall, Boca RatonCrossRefGoogle Scholar
  12. 12.
    Porreca F, Jiang Q, Tallarida RJ (1990) Modulation of morphine antinociception by peripheral [Leu5]enkephalin: a synergistic interaction. Eur J Pharmacol 179:463–468CrossRefPubMedGoogle Scholar
  13. 13.
    Borowicz KK, Swiader M, Luszczki J, Czuczwar SJ (2002) Effect of gabapentin on the anticonvulsant activity of antiepileptic drugs against electroconvulsions in mice: an isobolographic analysis. Epilepsia 43:956–963CrossRefPubMedGoogle Scholar
  14. 14.
    Luszczki JJ, Borowicz KK, Swiader M, Czuczwar SJ (2003) Interactions between oxcarbazepine and conventional antiepileptic drugs in the maximal electroshock test in mice: an isobolographic analysis. Epilepsia 44:489–499CrossRefPubMedGoogle Scholar
  15. 15.
    Luszczki JJ, Czuczwar SJ (2004) Isobolographic profile of interaction between tiagabine and gabapentin: a preclinical study. Naunyn Schmiedeberg’s Arch Pharmacol 369:434–446CrossRefGoogle Scholar
  16. 16.
    Löscher W, Fassbender CP, Nolting B (1991) The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. Epilepsy Res 8:171–189CrossRefPubMedGoogle Scholar
  17. 17.
    Monk JP, Brogden RN (1990) Mexiletine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias. Drugs 40:374–411CrossRefPubMedGoogle Scholar
  18. 18.
    Nelson LS, Hoffman RS (1994) Mexiletine overdose producing status epilepticus without cardiovascular abnormalities. J Toxicol Clin Toxicol 32:731–736CrossRefPubMedGoogle Scholar
  19. 19.
    Deckers CL, Czuczwar SJ, Hekster YA, Keyser A, Kubova H, Meinardi H, Patsalos PN, Renier WO, Van Rijn CM (2000) Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia 41:1364–1374CrossRefPubMedGoogle Scholar
  20. 20.
    Deckers CL, Genton P, Sills GJ, Schmidt D (2003) Current limitations of antiepileptic drug therapy: a conference review. Epilepsy Res 53:1–17CrossRefPubMedGoogle Scholar
  21. 21.
    Ragsdale DS, Avoli M (1998) Sodium channels as molecular targets for antiepileptic drugs. Brain Res Rev 26:16–28CrossRefPubMedGoogle Scholar
  22. 22.
    Czuczwar SJ, Patsalos PN (2001) The new generation of GABA enhancers. CNS Drugs 15:339–350CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Kinga K. Borowicz-Reutt
    • 1
  • Monika Banach
    • 1
  • Barbara Piskorska
    • 1
  1. 1.Independent Unit of Experimental Neuropathophysiology, Department of PathophysiologyMedical UniversityLublinPoland

Personalised recommendations