SCN1A and SCN1B gene polymorphisms and their association with plasma concentrations of carbamazepine and carbamazepine 10, 11 epoxide in Iranian epileptic patients

Document Type : Original Article


1 Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Pharmacotherapy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

3 Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

4 Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

5 Transgenic Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

6 Department of Neurology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran


Objective (s): From a genetic point of view, epilepsy is a polygenic multifactorial syndrome. The SCN1A and B genes belong to a family of genes that provide instructions for making sodium channels. Understanding the relevance of SCN1A and SCN1B gene polymorphisms to plasma concentration of carbamazepine (CBZ) and its active metabolite carbamazepine 10, 11 epoxide (CBZE), may shed more light on inter-individual variations in response to CBZ.
Materials and Methods: In this cross-sectional study, genotype distribution and  allele frequency of six non-synonymous exonic single nucleotide polymorphisms (SNPs) of the SCN1A  and B genes were selected  and determined using PCR-RFLP in 70 epileptic patients treated with CBZ for at least 6 months. The patients had no hepatic or renal diseases and received no medications known to have a major interaction with CBZ. Serum concentrations of CBZ and CBZE were measured using High-Performance Liquid Chromatography (HPLC).
Results: The AA, AG and GG alleles of SCN1A were found in 23, 37 and 10 patients, respectively. There were no statistically significant differences in the mean (± standard deviation) of plasma concentrations of CBZ (P=0.8) and CBZE (P=0.1) among these 3 groups.  Likewise, there was no statistically significant relationship between SCN1A polymorphisms and CBZ concentration/dose ratio (P=0.7). A significant association was found between CBZ plasma level and CBZ concentration/dose with CBZ daily dose. All patients had the same genotype of SCN1B gene(CC). and no statistical analysis was performed.
Conclusion: No significant association between SCN1A gene polymorphisms and plasma levels of CBZ and CBZE were found.


1. Ghaem H, Borhani-Haghighi A. Validity and reliability of the Persian epilepsy quality of life questionnaire. Neurosciences (Riyadh) 2010; 15:249-253.
2. Asadi-Pooya AA, Emami M, Ashjazadeh N, Nikseresht A, Shariat A, Petramfar P, et al. Reasons for uncontrolled seizures in adults; the impact of pseudointractability. Seizure 2013; 22:271-274.
3. Lakhan R, Kumari R, Misra UK, Kalita J, Pradhan S, Mittal B. Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population. Br J Clin Pharmacol 2009; 68:214-220.
4. Jang S, Kim M, Nam T, Kim J, Choi S, Lee S, et al. Polymorphisms in the voltage-gated sodium channel genes and  antiepileptic efficacy of  carbamazepine. J Korean Neurol Assoc. 2009; 27:147-153.
5. Yu FH, Catterall WA. Overview of the voltage-gated sodium channel family. Genome Biol 2003; 4:207.
6.Thompson CH, Kahlig KM, George AL Jr. SCN1A splice variants exhibit divergent sensitivity to commonly used antiepileptic drugs. Epilepsia 2011; 52:1000-1009.
7. Miller IO, Sotero de Menezes MA. SCN1A-related seizure disorders. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. Gene Reviews. Seattle (WA); 1993.
8. Toldo I, Bruson A, Casarin A, Salviati L, Boniver C, Sartori S, et al. Polymorphisms of the SCN1A gene in children and adolescents with primary headache and idiopathic or cryptogenic epilepsy: is there a linkage? J Headache Pain 2011; 12:435-441.
9. Zhou B, Zhou Q, Yin J, Li G, Xu X, Qu J, et al. Comprehensive analysis of the association of SCN1A gene polymorphisms with the retention rate of carbamazepine following monotherapy for new-onset focal seizures in the Chinese Han population. Clin Exp Pharmacol Physiol 2012; 39:379-384.
10. Heinzen EL, Woohyun Y, Tate SK, Sen A, Wood NW, Sisodiya SM, et al. Nova2 interacts with a cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A. Am J Hum Genet 2007; 80:876-883.
11. Uebachs M, Albus C, Opitz T, Isom L, Niespodziany I, Wolff C, et al. Loss of β1 accessory Na+ channel subunits causes failure of carbamazepine, but not of lacosamide, in blocking high-frequency firing via differential effects on persistent Na+ currents. Epilepsia 2012; 53:1959-1967.
12. Scheffer IE, Harkin LA, Grinton BE, Dibbens LM, Turner SJ, Zielinski MA, et al. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain 2007; 130:100-109.
13. Battino D, Estienne M, Avanzini G. Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part II. Phenytoin, carbamazepine, sulthiame, lamotrigine, vigabatrin, oxcarbazepine and felbamate. Clin Pharmacokinet 1995; 29:341-369.
14. Egnell A, Houston B, Boyer S. In vivo CYP3A4 heteroactivation is a possible mechanism for the drug interaction between felbamate and carbamazepine. J Pharmacol Exp Ther 2003; 305:1251-1262.
15. Sterjev Z, Kiteva G, Cvetkovska E, Petrov I, Kuzmanovski I, Ribarska T, et al. Influence of the SCN1A IVS5N + 5 G>A polymorphism on therapy with carbamazepine for epilepsy. Balkan J Med Genet 2012; 15:19-24.
16. Ragsdalea DS, Avoli M. Sodium channels as molecular targets for antiepileptic drugs. Brain Res  Rev 1998; 26:16–28.
17. Schirrmacher K, Mayer A, Walden J, Düsing R, Bingmann D. Effects of carbamazepine on membrane properties of rat sensory spinal ganglion cells in vitro. Eur Neuropsychopharmacol 1995; 5:501-507.
18. Namazi S, Borhani-Haghighi A, Karimzadeh I.Adverse reactions to antiepileptic drugs in epileptic outpatients: a cross-sectional study in Iran. Clin Neuropharmacol 2011; 34:79-83.
 19. Samaei A, Nobahar M, Vafaei AA. An experimental design for finding of minimum dosage of carbamazepine and valproate in preventing of seizure attacks. Pak J Pharm Sci 2009; 22:180-183.
20. Panayiotopoulos CP. The Epilepsies: seizures, synd-romes and management. Oxfordshire (UK); 2005.
21. Guidance for Industry, drug-induced liver injury: Premarketing clinical evaluation. 2009.
22. Bagshaw SM, Mortis G, Doig CJ, Godinez-Luna T, Fick GH, Laupland KB. One-year mortality in critically ill patients by severity of kidney dysfunction: A population-based assessment. Am J Kidney Dis 2006; 48:402-409.
23. Fong SY, Gao Q, Zuo Z. Interaction of carbamazepine with herbs, dietary supplements, and food: A Systematic Review. Evid Based Complement Alternat Med 2013; 2013:898261.
24. Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. Clin- Pharmacokinet 1996; 31:198-214.
25. Uijla SG, Uiterwaalb CSMP, Aldenkampc AP, Carpayd JA, Doelmane JC, Keizerf K, et al. A cross-sectional study of subjective complaints in patients with epilepsy who seem to be well-controlled with anti-epileptic drugs. Seizure 2006; 15:242–248.
26. Chou IC PC, Tsai FJ. The lack of assossiation between febrile convulsions and polymorphisms in SCN1A. Epilepsy  Res 2003; 54:53-57.
27. Kwan P, Brodie MJ. Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 2001; 357:216-222.
28. Asadi-Pooya AA, Shokouhyar S, Emami M, Sharifzade M. Perception and use of complementary and alternative medicine among patients with epilepsy. Arch Neurosci 2013; 1:60-66.
29. Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N, et al. Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci USA 2005; 102:5507-5512.
30. Hung CC, Chang WL, Ho JL, Tai JJ, Hsieh TJ, Huang HC,  et al. Association of polymorphisms in EPHX1, UGT2B7, ABCB1, ABCC2, SCN1A and SCN2A genes with carbamazepine therapy optimization. Pharmacogenomics 2012; 13:159-169.
31.Zimprich F, Stogmann E, Bonelli S, Baumgartner C, Mueller JC, Meitinger T, et al. A functional polymorphism in the SCN1A gene is not associated with carbamazepine dosages in Austrian patients with epilepsy. Epilepsia 2008; 49:1108-1109.
32. Haerian BS, Baum L, Kwan P, Tan HJ, Raymond AA, Mohamed Z. SCN1A, SCN2A and SCN3A gene polymorphisms and responsiveness to antiepileptic drugs: a multicenter cohort study and meta-analysis. Pharmacogenomics 2013; 14:1153-1166.
33. Wang M, Sang S, Hwang LS, Ho C-T. Herbs, Challenges in Chemistry and Biology, ACS symposium series 925. 2006:xii, 369p.
34. Chan E, Lee HS, Hue SS. Population pharmacokinetics of carbamazepine in Singapore epileptic patients. Br J Clin Pharmacol 2001; 51:567-576.
35. Liu H, Delgado M. Influence of sex, age, weight, and carbamazepine dose on serum concentrations, concentration ratios, and level/dose ratios of carbamazepine and its metabolites. Ther Drug Monit 1994; 16:469-476.