Abstract
Carbamazepine (CBZ) is a first-line widely used anticonvulsant. It has a narrow therapeutic index and exhibits considerable interindividual and interethnic variability in clinical efficacy and adverse drug reactions including potentially life-threatening hypersensitivity reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The most important pharmacogenetic finding is related to the association of CBZ-induced hypersensitivity with human leukocyte antigens (HLA class I and II alleles). Moreover, genotyping for HLA-B*15:02 allele is required prior to initiating CBZ in Asians and Asian ancestry patients, demonstrating the usefulness of biomarkers to avoid adverse drug reactions. On the other hand, in order to explain the differences in the clinical response to CBZ, genetic polymorphisms in phase I (CYP3A4, CYP3A5 and EPHX1) and phase II (UGT2B7) metabolising enzymes have been assessed; additionally, the influence of transporters (ABCB1 and ABCC2), receptors (PXR) and other drug targets (voltage- gated Na+ channels) in CBZ clinical response has been evaluated. To date, these studies are controversial and require further investigations to clarify the functional role of these polymorphisms as potential biomarkers in regard to CBZ therapy.
Acknowledgments
The study has been partly supported by a grant from Consejo Nacional de Ciencia y Tecnología de México (CONACYT #167261); and by the Institute of Health Carlos III-FIS and the European Union (FEDER) Grants PI10/02758 and Gobierno de Extremadura AEXCID Cooperación Extremeña (11IA002); and was coordinated in the SIFF-RIBEF network (Red Iberoamericana de Farmacogenética y Farmacogenómica; www.ribef.com).
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflict of interest regarding the publication of this article. Research support played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the report for publication.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
References
1. Brodie MJ, Dichter MA. Established antiepileptic drugs. Seizure 1997;6:159–74.10.1016/S1059-1311(97)80001-5Search in Google Scholar
2. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder. Am J Psychiatry 2002;159(Suppl):S1–50.Search in Google Scholar
3. Yukawa E. Investigation of phenobarbital-carbamazepine-valproic acid interactions using population pharmacokinetic analysis for optimisation of antiepileptic drug therapy: an overview. Drug Metabol Drug Interact 2000;16:86–98.10.1515/DMDI.2000.16.2.85Search in Google Scholar
4. McMillin GA, Juenke JM, Tso G, Dasgupta A. Estimation of carbamazepine and carbamazepine-10,11-epoxide concentrations in plasma using mathematical equations generated with two carbamazepine immunoassays. Am J Clin Pathol 2010;133:728–36.10.1309/AJCPFAHVB26VVVTESearch in Google Scholar
5. Furst S, Uetrecht J. Carbamazepine metabolism to a reactive intermediate by the myeloperoxidase system of activated neutrophils. Biochem Pharmacol 1993;45:1267–75.10.1016/0006-2952(93)90279-6Search in Google Scholar
6. Ju C, Uetrecht JP. Detection of 2-Hydroxyiminostilbene in the urine of patients taking carbamazepine and its oxidation to a reactive iminoquinone intermediate. J Pharmacol Exp Ther 1999;288:51–6.Search in Google Scholar
7. Staines AG, Coughtrie MW, Burchell B. N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. J Pharmacol Exp Ther 2004;311:1131–7.10.1124/jpet.104.073114Search in Google Scholar
8. Kudriakova TB, Sirota LA, Rozova GI, Gorkov VA. Autoinduction and steady-state pharmacokinetics of carbamazepine and its major metabolites. Br J Clin Pharmacol 1992; 33:611–5.10.1111/j.1365-2125.1992.tb04089.xSearch in Google Scholar
9. Johannessen S, Johanessen C. Antiepileptic drug interactions – Principles and clinical implications. Current Neuropharmacol 2010;8:254–7.10.2174/157015910792246254Search in Google Scholar
10. Okey AB. Enzyme induction in the cytochrome P-450 system. Pharmacol Ther 1990;45:241–98.10.1016/0163-7258(90)90030-6Search in Google Scholar
11. Macdonald RL, Kelly KM. Antiepileptic drug mechanisms of action. Epilepsia 1995;36(Suppl):S2–12.10.1111/j.1528-1157.1995.tb05996.xSearch in Google Scholar PubMed
12. Leckband SG, Kelsoe JR, Dunnenberger HM, George AL, Tran E, Berger R, et al. Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther 2013;May 21. doi: 10.1038/clpt.2013.103 [Epub ahead of print].10.1038/clpt.2013.103Search in Google Scholar PubMed PubMed Central
13. Shastry CS, Shafeeque AA, Ashwathnarayana BJ. Effect of combination of aripiprazole with carbamazepine and fluvoxamine on liver functions in experimental animals. Indian J Pharmacol 2013;45:121–5.10.4103/0253-7613.108280Search in Google Scholar
14. Ferner RE, Butt TF. Adverse drug reactions. Medicine 2012;40:366–70.10.1016/j.mpmed.2012.05.001Search in Google Scholar
15. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007;369:1000–15.10.1016/S0140-6736(07)60460-7Search in Google Scholar
16. Ozaras N, Goksugur N, Eroglu S, Tabak O, Canbakan B, Ozaras R. Carbamazepine-induced hypogammaglobulinemia. Seizure 2012;21:229–31.10.1016/j.seizure.2011.12.013Search in Google Scholar PubMed
17. Jamal MA. Factors affecting the development of adverse drug reactions. Saudi Pharmaceutical J 2013;[article in press]. http://dx.doi.org/10.1016/j.jsps.2013.02.003.10.1016/j.jsps.2013.02.003Search in Google Scholar PubMed PubMed Central
18. Perucca E, Hedges A, Makki KA, Ruprah M, Wilson JF, Richens A. A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients. Br J Clin Pharmacol 1984;18:401–10.10.1111/j.1365-2125.1984.tb02482.xSearch in Google Scholar PubMed PubMed Central
19. Yasuda SU, Zhang L, Huang SM. The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies. Clin Pharmacol Ther 2008;84:417–23.10.1038/clpt.2008.141Search in Google Scholar PubMed
20. Aldaz A, Ferriols R, Aumente D, Calvo MV, Farre MR, García B, et al. Pharmacokinetic monitoring of antiepileptic drugs. Farm Hosp 2011;35:326–39.10.1016/j.farma.2010.10.005Search in Google Scholar PubMed
21. Daly AK. Genetic polymorphisms affecting drug metabolism: recent advances and clinical aspects. Adv Pharmacol 2012;63:137–67.10.1016/B978-0-12-398339-8.00004-5Search in Google Scholar PubMed
22. Stern R. Exanthematous drug eruptions. N Engl J Med 2012;366:2492–501.10.1056/NEJMcp1104080Search in Google Scholar PubMed
23. Hung SI, Chung WH, Liu ZS, Chen CH, Hsih MS, Hui RC, et al. Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics 2010;11:349–56.10.2217/pgs.09.162Search in Google Scholar PubMed
24. Yip VL, Marson AG, Jorgensen AL, Pirmohamed M, Alfirevic A. HLA genotype and carbamazepine-induced cutaneous adverse drug reactions: a systematic review. Clin Pharmacol Ther 2012;92:757–65.10.1038/clpt.2012.189Search in Google Scholar PubMed
25. Man C, Kwan P, Baum L, Yu E, Lau KM, Cheng A, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia 2007;48:1015–8.10.1111/j.1528-1167.2007.01022.xSearch in Google Scholar PubMed
26. Ahijara M. Pharmacogenetics of cutaneous adverse drug reactions. J Dermatol 2011;38:246–54.10.1111/j.1346-8138.2010.01196.xSearch in Google Scholar PubMed
27. Chung WH, Hung SI, Hong HS, Hsih M-S, Yang L-C, Ho H-C, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428:486.10.1038/428486aSearch in Google Scholar PubMed
28. U.S. Food and Drug Administration. FDA Safety Alerts for Human Medical Products. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150841.htm. Accessed December 2, 2013.Search in Google Scholar
29. McCormack M, Alfirevic A, Bourgeois S, Farrel JJ, Kasperavičiūt D, Carrington M. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011;364:1134–43.10.1056/NEJMoa1013297Search in Google Scholar PubMed PubMed Central
30. Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia 2008;49:2087–91.10.1111/j.1528-1167.2008.01719.xSearch in Google Scholar PubMed
31. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, et al. HLA-B*1511 is a risk factor for carbamazepine-induced Stevens Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Epilepsia 2010;51:2461–65.10.1111/j.1528-1167.2010.02766.xSearch in Google Scholar PubMed
32. Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006;16:297–306.10.1097/01.fpc.0000199500.46842.4aSearch in Google Scholar PubMed
33. Kim SH, Lee KW, Song WJ, Kim SH, Jee YK, Lee SM, et al. Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans. Epilepsy Res 2011;97:190–7.10.1016/j.eplepsyres.2011.08.010Search in Google Scholar PubMed
34. Ozeki T, Mushiroda T, Yowang A, Takahashi A, Kubo M, Shirakata Y, et al. Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet 2011;20:1034–41.10.1093/hmg/ddq537Search in Google Scholar PubMed
35. Li LJ, Hu FY, Wu XT, An DM, Yan B, Zhoy D. Predictive markers for carbamazepine and lamotrigine-induced maculopapular exantherma in Han Chinese. Epilepsy Res 2013; pii: S0920–1211(13)00144-7. doi: 10.1016/j.eplepsyres.2013.05.004. [Epub ahead of print].10.1016/j.eplepsyres.2013.05.004Search in Google Scholar PubMed
36. Pirmohamed M, Lin K, Chadwick D, Park BK. TNFalpha promoter region gene polymorphisms in carbamazepine-hypersensitive patients. Neurology 2001;56:890–6.10.1212/WNL.56.7.890Search in Google Scholar PubMed
37. Alfiveric A, Mills T, Harrington P, Pinel T, Sherwood J, Jawaid A, et al. Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster. Pharmacogenet Genomics 2006;16:287–96.10.1097/01.fpc.0000189800.88596.7aSearch in Google Scholar PubMed
38. Thorn CF, Leckband SG, Kelsoe J, Leeder JS, Müller DJ, Klein TE, et al. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011;21:906–10.10.1097/FPC.0b013e328348c6f2Search in Google Scholar PubMed PubMed Central
39. Puranik YG, Birnbaum AK, Marino SE, Ahmed G, Cloyd JC, Remmel RP, et al. Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy. Pharmacogenomics 2013;14:35–45.10.2217/pgs.12.180Search in Google Scholar PubMed PubMed Central
40. Park PW, Seo YH, Ahn JY, Kim KA, Park JY. Effect of CYP3A5*3 genotype on serum carbamazepine concentrations at steady-state in Korean epileptic patients. J Clin Pharm Ther 2009;34:569–74.10.1111/j.1365-2710.2009.01057.xSearch in Google Scholar PubMed
41. Seo T, Nakada N, Ueda N, Hagiwara T, Hashimoto N, Nakagawa K, et al. Effect of CYP3A5*3 on carbamazepine pharmacokinetics in Japanese patients with epilepsy. Clin Pharmacol Ther 2006;79:509–10.10.1016/j.clpt.2006.02.009Search in Google Scholar PubMed
42. 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;13:159–69.10.2217/pgs.11.141Search in Google Scholar PubMed
43. Nakajima Y, Saito Y, Shiseki K, Fukushima-Uesaka H, Hasegawa R, Ozawa S, et al. Haplotype structures of EPHX1 and their effects on the metabolism of carbamazepine-10,11-epoxide in Japanese epileptic patients. Eur J Clin Pharmacol 2005;61: 25–34.10.1007/s00228-004-0878-1Search in Google Scholar PubMed
44. Sánchez MB, Herranz JL, Leno C, Arteaga R, Oterino A, Valdizán EM, et al. UGT2B7_-161C>T polymorphism is associated with lamotrigine concentration-to-dose ratio in a multivariate study. Ther Drug Monit 2010;32:177–84.10.1097/FTD.0b013e3181ceecc6Search in Google Scholar PubMed
45. Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 2003;348:1442–8.10.1056/NEJMoa021986Search in Google Scholar PubMed
46. Sterjev Z, Trencevska GK, Cvetkovska E, Petrov I, Kuzmanovski I, Ribarska JT, et al. The association of C3435T single-nucleotide polymorphism, Pgp-glycoprotein gene expression levels and carbamazepine maintenance dose in patients with epilepsy. Neuropsychiatr Dis Treat 2012;8:191–6.Search in Google Scholar
47. Sánchez MB, Herranz JL, Leno C, Arteaga R, Oterino A, Valdizán EM, et al. Genetic factors associated with drug-resistance of epilepsy: relevance of stratification by patient age and aetiology of epilepsy. Seizure 2010;19:93–101.10.1016/j.seizure.2009.12.004Search in Google Scholar PubMed
48. Kim WJ, Lee JH, Yi J, Cho YJ, Heo K, Lee SH, et al. A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy. Pharmacogenet Genomics 2010;20: 249–56.10.1097/FPC.0b013e328338073aSearch in Google Scholar PubMed
49. Bournissen FG, Moretti ME, Juurlink DN, Koren G, Walker M, Finkelstein Y. Polymorphism of the MDR1/ABCB1 C3435T drug-transporter and resistance to anticonvulsant drugs: a meta-analysis. Epilepsia 2009;50:898–903.10.1111/j.1528-1167.2008.01858.xSearch in Google Scholar PubMed
50. Awasthi S, Hallene KL, Fazio V, Singhal SS, Cucullo L, Awasthi YC, et al. RLIP76, a non-ABC transporter, and drug resistance in epilepsy. BMC Neurosci 2005;6:61.10.1186/1471-2202-6-61Search in Google Scholar PubMed PubMed Central
51. Soranzo N, Kelly L, Martinian L, Burley MW, Thom M, Sali A, et al. Lack of support for a role for RLIP76 (RALBP1) in response to treatment or predisposition to epilepsy. Epilepsia 2007;48:674–83.10.1111/j.1528-1167.2007.00926.xSearch in Google Scholar PubMed
52. Leschziner GD, Jorgensen AL, Andrew T, Williamson PR, Marson AG, Coffey AJ, et al. The association between polymorphisms in RLIP76 and drug response in epilepsy. Pharmacogenomics 2007;8:1715–22.10.2217/14622416.8.12.1715Search in Google Scholar PubMed
53. Ufer M, von Stülpnagel C, Muhle H, Haenisch S, Remmler C, Majed A, et al. Impact of ABCC2 genotype on antiepileptic drug response in Caucasian patients with childhood epilepsy. Pharmacogenet Genomics 2011;21:624–30.10.1097/FPC.0b013e3283498131Search in Google Scholar PubMed
54. Zhou BT, Zhou QH, Yin JY, Li GL, Qu J, Xu XJ, et al. Effects of SCN1A and GABA receptor genetic polymorphisms on carbamazepine tolerability and efficacy in Chinese patients with partial seizures: 2-year longitudinal clinical follow-up. CNS Neurosci Ther 2012;18:566–72.10.1111/j.1755-5949.2012.00321.xSearch in Google Scholar PubMed PubMed Central
55. 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;102:5507–12.10.1073/pnas.0407346102Search in Google Scholar PubMed PubMed Central
56. Abe T, Seo T, Ishitsu T, Nakagawa T, Hori M, Nakagawa K. Association between SCN1A polymorphism and carbamazepine-resistant epilepsy. Br J Clin Pharmacol 2008;66:304–7.10.1111/j.1365-2125.2008.03203.xSearch in Google Scholar PubMed PubMed Central
57. Kumari R, Lakhan R, Kumar S, Garg RK, Misra UK, Kalita J, et al. SCN1AIVS5-91G>A polymorphism is associated with susceptibility to epilepsy but not with drug responsiveness. Biochimie 2013;95:1350–3.10.1016/j.biochi.2013.02.006Search in Google Scholar PubMed
58. Kwan P, Poon WS, Ng HK, Kang DE, Wong V, Ng PW, et al. Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: correlation among phenotype, genotype, and mRNA expression. Pharmacogenet Genomics 2008;18:989–98.10.1097/FPC.0b013e3283117d67Search in Google Scholar PubMed
59. Kumari R, Lakhan R, Kalita J, Misra UK, Mittal B. Association of alpha subunit of GABAA receptor subtype gene polymorphisms with epilepsy susceptibility and drug resistance in north Indian population. Seizure 2010;19:237–41.10.1016/j.seizure.2010.02.009Search in Google Scholar PubMed
60. Kumari R, Lakhan R, Kalita J, Garg RK, Misra UK, Mittal B. Potential role of GABAA receptor subunit; GABRA6, GABRB2 and GABRR2 gene polymorphisms in epilepsy susceptibility and pharmacotherapy in North Indian population. Clin Chim Acta 2011;412:1244–8.10.1016/j.cca.2011.03.018Search in Google Scholar PubMed
61. Simon C, Stieger B, Kullak-Ublick GA, Fried M, Mueller S, Fritschy JM, et al. Intestinal expression of cytochrome P450 enzymes and ABC transporters and carbamazepine and phenytoin disposition. Acta Neurol Scand 2007;115:232–42.10.1111/j.1600-0404.2006.00761.xSearch in Google Scholar PubMed
62. Maekawa K, Yoshimura T, Saito Y, Fujimura Y, Aohara F, Emoto C, et al. Functional characterization of CYP3A4.16: catalytic activities toward midazolam and carbamazepine. Xenobiotica 2009;39:140–7.10.1080/00498250802617746Search in Google Scholar PubMed
63. Maekawa K, Harakawa N, Yoshimura T, Kim SR, Fujimura Y, Aohara F, et al. CYP3A4*16 and CYP3A4*18 alleles found in East Asians exhibit differential catalytic activities for seven CYP3A4 substrate drugs. Drug Metab Dispos 2010;38:2100–4.10.1124/dmd.110.034140Search in Google Scholar PubMed
64. Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos 2002;30:883–91.10.1124/dmd.30.8.883Search in Google Scholar PubMed
65. Makmor-Bakry M, Sills GJ, Hitiris N, Butler E, Wilson EA, Brodie MJ. Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing. Clin Neuropharmacol 2009;32:205–12.10.1097/WNF.0b013e318187972aSearch in Google Scholar PubMed
66. Bauer JE, Gerber N, Lynn RK, Smith RG, Thompson RM. A new N-glucuronide metabolite of carbamazepine. Experientia 1976;32:1032–3.10.1007/BF01933954Search in Google Scholar PubMed
67. Maggs JL, Pirmohamed M, Kitteringham NR, Park BK. Characterization of the metabolites of carbamazepine in patient urine by liquid chromatography mass spectrometry. Drug Metab Dispos 1997;25:275–80.Search in Google Scholar
68. Bhasker CR, McKinnon W, Stone A, Lo AC, Kubota T, Ishizaki T, et al. Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Pharmacogenetics 2000 Nov;10:679.10.1097/00008571-200011000-00002Search in Google Scholar PubMed
69. Innocenti F, Liu W, Fackenthal D, Ramírez J, Chen P, Ye X, et al. Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene. Pharmacogenet Genomics 2008;18:683–97.10.1097/FPC.0b013e3283037fe4Search in Google Scholar PubMed PubMed Central
70. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–9.10.1056/NEJM200002033420503Search in Google Scholar PubMed
71. Lazarowski A, Czornyj L. Potential role of multidrug resistant proteins in refractory epilepsy and antiepileptic drugs interactions. Drug Metabol Drug Interact 2011;26:21–6.10.1515/dmdi.2011.006Search in Google Scholar
72. Beck H. Plasticity of antiepileptic drug targets. Epilepsia 2007;48(Suppl):S14–8.10.1111/j.1528-1167.2007.00994.xSearch in Google Scholar PubMed
73. Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 2005;6:591–602.10.1038/nrn1728Search in Google Scholar PubMed
74. Haerian BS, Roslan H, Raymond AA, Tan CT, Lim KS, Zulkifli SZ, et al. ABCB1 C3435T polymorphism and the risk of resistance to antiepileptic drugs in epilepsy: a systematic review and meta-analysis. Seizure 2010;19:339–46.10.1016/j.seizure.2010.05.004Search in Google Scholar PubMed
75. Nurmohamed L, Garcia-Bournissen F, Buono RJ, Shannon MW, Finkelstein Y. Predisposition to epilepsy – does the ABCB1 gene play a role? Epilepsia 2010;51:1882–5.10.1111/j.1528-1167.2010.02588.xSearch in Google Scholar PubMed
76. Potschka H, Fedrowitz M, Löscher W. Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther 2003;306:124–31.10.1124/jpet.103.049858Search in Google Scholar PubMed
77. Subenthiran S, Abdullah NR, Joseph JP, Muniandy PK, Mok BT, Kee CC, et al. Linkage disequilibrium between polymorphisms of ABCB1 and ABCC2 to predict the treatment outcome of Malaysians with complex partial seizures on treatment with carbamazepine mono-therapy at the Kuala Lumpur Hospital. PLoS One 2013;8:e64827.10.1371/journal.pone.0064827Search in Google Scholar PubMed PubMed Central
78. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J, Johne A, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000;97:3473–8.10.1073/pnas.97.7.3473Search in Google Scholar PubMed PubMed Central
79. Nakamura T, Sakaeda T, Horinouchi M, Tamura T, Aoyama N, Shirakawa T, et al. Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther 2002;71:297–303.10.1067/mcp.2002.122055Search in Google Scholar PubMed
80. Ozgon GO, Bebek N, Gul G, Cine N. Association of MDR1 (C3435T) polymorphism and resistance to carbamazepine in epileptic patients from Turkey. Eur Neurol 2008;59:67–70.10.1159/000109264Search in Google Scholar PubMed
81. Meng H, Guo G, Ren J, Zhou H, Ge Y, Guo Y. Effects of ABCB1 polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy. Epilepsy Behav 2011;21:27–30.10.1016/j.yebeh.2011.02.015Search in Google Scholar PubMed
82. Ufer M, Mosyagin I, Muhle H, Jacobsen T, Haenisch S, Häsler R, et al. Non-response to antiepileptic pharmacotherapy is associated with the ABCC2 -24C>T polymorphism in young and adult patients with epilepsy. Pharmacogenet Genomics 2009;19:353–62.10.1097/FPC.0b013e328329940bSearch in Google Scholar
83. Hung CC, Chiou MH, Huang BH, Hsieh YW, Hsieh TJ, Huang CL, et al. Impact of genetic polymorphisms in ABCB1, CYP2B6, OPRM1, ANKK1 and DRD2 genes on methadone therapy in Han Chinese patients. Pharmacogenomics 2011;12:1525–33.10.2217/pgs.11.96Search in Google Scholar PubMed
84. Depondt C. Epilepsy pharmacogenetics: science or fiction?. Med Sci 2013;29:189–93.Search in Google Scholar
85. Dickens D, Yusof SR, Abbott NJ, Weksler B, Romero IA, Couraud PO, et al. A multi-system approach assessing the interaction of anticonvulsants with P-gp. PLoS One 2013;8:64854.10.1371/journal.pone.0064854Search in Google Scholar PubMed PubMed Central
86. Krasowski MD. Therapeutic drug monitoring of the newer anti-epilepsy medications. Pharmaceuticals (Basel) 2010 Jun;3:1909–35.10.3390/ph3061909Search in Google Scholar PubMed PubMed Central
87. Hung CC, Jen Tai J, Kao PJ, Lin MS, Liou HH. Association of polymorphisms in NR1I2 and ABCB1 genes with epilepsy treatment responses. Pharmacogenomics 2007;8:1151–8.10.2217/14622416.8.9.1151Search in Google Scholar
88. Haerian BS, Lim KS, Mohamed EH, Tan HJ, Tan CT, Raymond AA, et al. Lack of association of ABCB1 and PXR polymorphisms with response to treatment in epilepsy. Seizure 2011;20:387–94.10.1016/j.seizure.2011.01.008Search in Google Scholar
89. Catterall WA. From ionic currents to molecular mechanisms: The structure and function of voltage-gated sodium channels. Neuron 2000;26:13–25.10.1016/S0896-6273(00)81133-2Search in Google Scholar
90. Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol 2010;588:1849–59.10.1113/jphysiol.2010.187484Search in Google Scholar PubMed PubMed Central
91. Tate SK, Singh R, Hung CC, Tai JJ, Depondt C, Cavalleri GL, et al. A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose. Pharmacogenet Genomics 2006;16:721–26.10.1097/01.fpc.0000230114.41828.73Search in Google Scholar PubMed
92. Heinzen EL, Yoon W, 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;80:876–83.10.1086/516650Search in Google Scholar PubMed PubMed Central
93. Song W, Liu Z, Tan J, Nomura Y, Dong K. RNA editing generates tissue-specific sodium channels with distinct gating properties. J Biol Chem 2004;279:32554–61.10.1074/jbc.M402392200Search in Google Scholar PubMed PubMed Central
94. 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: 1108–9.10.1111/j.1528-1167.2008.01549_4.xSearch in Google Scholar PubMed
95. Manna I, Gambardella A, Bianchi A, Striano P, Tozzi R, Aguglia U, et al. A functional polymorphism in the SCN1A gene does not influence antiepileptic drug responsiveness in Italian patients with focal epilepsy. Epilepsia 2011;52:40–4.10.1111/j.1528-1167.2011.03097.xSearch in Google Scholar PubMed
96. Sills G, Mohanraj R, Butler E. A single-nucleotide polymorphism in the SCN2A gene is associated with uncontrolled epilepsy. Epilepsia 2004;45:(Suppl):S226.Search in Google Scholar
97. 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: 214–20.10.1111/j.1365-2125.2009.03437.xSearch in Google Scholar PubMed PubMed Central
98. Uebachs M, Opitz T, Royeck M, Dickhof G, Horstmann MT, Isom LL, et al. Efficacy loss of the anticonvulsant carbamazepine in mice lacking sodium channel beta subunits via paradoxical effects on persistent sodium currents. J Neurosci 2010;30:8489–501.10.1523/JNEUROSCI.1534-10.2010Search in Google Scholar PubMed PubMed Central
©2014 by Walter de Gruyter Berlin/Boston
