Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy


Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A4*1b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A4*1b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.

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Fig. 1: Analysis of UGT1A4 variants.
Fig. 2: Box and whiskers (min. to max.) plots of lamotrigine (LTG) plasma concentration.


  1. 1.

    Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:512–21.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Leach MJ, Marden CM, Miller AA. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia. 1986;27:490–97.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Singkham N, Towanabut S, Lertkachatarn S, Punyawudho B. Influence of the UGT2B7 -161C>T polymorphism on the population pharmacokinetics of lamotrigine in Thai patients. Eur J Clin Pharm. 2013;69:1285–91.

    CAS  Article  Google Scholar 

  4. 4.

    Garnett WR. Lamotrigine: pharmacokinetics. J Child Neurol. 1997;12:S10–5.

    PubMed  Article  Google Scholar 

  5. 5.

    Inoue K, Yamamoto Y, Suzuki E, Takahashi T, Umemura A, Takahashi Y, et al. Factors that influence the pharmacokinetics of lamotrigine in Japanese patients with epilepsy. Eur J Clin Pharm. 2016;72:555–62.

    CAS  Article  Google Scholar 

  6. 6.

    European Medicines Agency. Available from: Accessed 18 Apr 2019.

  7. 7.

    U.S. Food & Drug Administration. Available from: Accessed 18 Apr 2019.

  8. 8.

    Rowland A, Elliot DJ, Williams JA, Mackenzie PI, Dickinson RG, Miners JO. In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine valproic acid interaction. Drug Metab Dispos. 2006;34:1055–62.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    UGT alleles Nomenclature. Available from: Accessed 20 Oct 2018.

  10. 10.

    Gulcebi MI, Ozkaynakcı A, Goren MZ, Aker RG, Ozkara C, Onat FY. The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy. Epilepsy Res. 2011;95:1–8.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    López M, Dorado P, Ortega A, Peñas-Lledó E, Monroy N, Silva-Zolezzi I, et al. Interethnic differences in UGT1A4 genetic polymorphisms between Mexican Mestizo and Spanish populations. Mol Biol Rep. 2013;40:3187–92.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Wang Q, Liang M, Dong Y, Yun W, Qiu F, Zhao L, et al. Effects of UGT1A4 genetic polymorphisms on serum lamotrigine concentrations in Chinese children with epilepsy. Drug Metab Pharmacokinet. 2015;30:209–13.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Ehmer U, Vogel A, Schütte JK, Krone B, Manns MP, Strassburg CP. Variation of hepatic glucuronidation: novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4. Hepatology. 2004;39:970–7.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Benoit-Biancamano MO, Adam JP, Bernard O, Court MH, Leblanc MH, Caron P, et al. A pharmacogenetics study of the human glucuronosyltransferase UGT1A4. Pharmacogenet Genom. 2009;19:945–54.

    CAS  Article  Google Scholar 

  15. 15.

    Zhou J, Argikar UA, Remmel RP. Functional analysis of UGT1A4 (P24T) and UGT1A4 (L48 V) variant enzymes. Pharmacogenomics. 2011;12:1671–79.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Chang Y, Yang LY, Zhang MC, Liu SY. Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China. Eur J Clin Pharm. 2014;70:941–6.

    CAS  Article  Google Scholar 

  17. 17.

    Du Z, Jiao Y, Shi L. Association of UGT2B7 and UGT1A4 Polymorphisms with Serum Concentration of Antiepileptic Drugs in Children. Med Sci Monit. 2016;22:4107–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Chen Y, Xu S, Wang Z, Zhao M, Wang H, Lu T, et al. A population pharmacokinetic-pharmacogenetic model of lamotrigine in Chinese children with epilepsy. Ther Drug Monit. 2018;40:730–7.

    CAS  PubMed  Google Scholar 

  19. 19.

    Milosheska D, Lorber B, Vovk T, Kastelic M, Dolžan V, Grabnar I. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: influence of polymorphism of UDP-glucuronosyltransferases and drug transporters. Br J Clin Pharm. 2016;82:399–411.

    CAS  Article  Google Scholar 

  20. 20.

    Reimers A, Sjursen W, Helde G, Brodtkorb E. Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine. Eur J Drug Metab Pharmacokinet. 2016;41:149–55.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Kim SC, Kim MG. Meta-analysis of the Influence of UGT Genetic Polymorphisms on Lamotrigine Concentration. Basic Clin Pharm Toxicol. 2019;124:163–9.

    CAS  Article  Google Scholar 

  22. 22.

    Blanca Sánchez M, 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.

    PubMed  Google Scholar 

  23. 23.

    Barbarino JM, Haidar CE, Klein TE, Altman RB. PharmGKB summary: very important pharmacogene information for UGT1A1. Pharmacogenet Genom. 2014;24:177–83.

    CAS  Article  Google Scholar 

  24. 24.

    Luna-Tortós C, Fedrowitz M, Löscher W. Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology. 2008;55:1364–75.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Zhou Y, Wang X, Li H, Zhang J, Chen Z, Xie W, et al. Polymorphisms of ABCG2, ABCB1 and HNF4α are associated with Lamotrigine trough concentrations in epilepsy patients. Drug Metab Pharmacokinet. 2015;30:282–7.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Lovrić M, Božina N, Hajnšek S, Kuzman MR, Sporiš D, Lalić Z, et al. Association between lamotrigine concentrations and ABCB1 polymorphisms in patients with epilepsy. Ther Drug Monit. 2012;34:518–25.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Kim R, Leake B, Choo E, Dresser G, Kubba S, Schwarz U, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharm Ther. 2001;70:189–99.

    CAS  Article  Google Scholar 

  28. 28.

    Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharm Ther. 2004;75:13–33.

    CAS  Article  Google Scholar 

  29. 29.

    Römermann K, Helmer R, Löscher W. The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2). Neuropharmacology. 2015;93:7–14.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Shen CH, Zhang YX, Lu RY, Jin B, Wang S, Liu ZR, et al. Specific OCT1 and ABCG2 polymorphisms are associated with lamotrigine concentrations in Chinese patients with epilepsy. Epilepsy Res. 2016;127:186–90.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Klarica Domjanović I, Lovrić M, Trkulja V, Petelin-Gadže Ž, Ganoci L, Čajić I, et al. Interaction between ABCG2 421C>A polymorphism and valproate in their effects on steady-state disposition of lamotrigine in adults with epilepsy. Br J Clin Pharm. 2018;84:2106–19.

    Article  CAS  Google Scholar 

  32. 32.

    Dickens D, Owen A, Alfirevic A, Giannoudis A, Davies A, Weksler B, et al. Lamotrigine is a substrate for OCT1 in brain endothelial cells. Biochem Pharmacol. 2012;83:805–14.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Saeki M, Saito Y, Jinno H, Sai K, Hachisuka A, Kaniwa N, et al. Genetic variations and haplotypes of UGT1A4 in a Japanese population. Drug Metab Pharmacokinet. 2005;20:144–51.

    PubMed  Article  Google Scholar 

  34. 34.

    Morris RG, Black AB, Harris AL, Batty AB, Sallustio BC. Lamotrigine and therapeutic drug monitoring: retrospective survey following the introduction of a routine service. Br J Clin Pharm. 1998;46:547–51.

    CAS  Article  Google Scholar 

  35. 35.

    Douglas-Hall P, Dzahini O, Gaughran F, Bile A, Taylor D. Variation in dose and plasma level of lamotrigine in patients discharged from a mental health trust. Ther Adv Psychopharmacol. 2017;7:17–24.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Koristkova B, Grundmann M, Brozmanova H, Kacirova I. Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients. Basic Clin Pharm Toxicol. 2019;125:26–33.

    CAS  Article  Google Scholar 

  37. 37.

    Lovrić M, Čajić I, Petelin Gadže Ž, Klarica Domjanović I, Božina N. Effect of antiepileptic drug comedication on lamotrigine concentrations. Croat Med J. 2018;59:13–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Martínez-Juárez IE, López-Zapata R, Gómez-Arias B, Bravo-Armenta E, Romero-Ocampo L, Estévez-Cruz Z, et al. Epilepsia farmacorresistente: uso de la nueva definición y factores de riesgo relacionados. Estudio en población mexicana de un Cent de Terc Niv Rev Neurol. 2012;54:159–66.

    Google Scholar 

  39. 39.

    Ramaratnam S, Panebianco M, Marson AG. Lamotrigine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev. 2016;6:CD001909.

    Google Scholar 

  40. 40.

    Bootsma HP, Vos AM, Hulsman J, Lambrechts D, Leenen L, Majoie M, et al. Lamotrigine in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center. Epilepsy Behav 2008;12:262–8.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Kanner AM, Frey M. Adding valproate to lamotrigine: a study of their pharmacokinetic interaction. Neurology. 2000;55:588–91.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol. 2003;2:347–56.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Rivas N, Buelga DS, Elger CE, Santos-Borbujo J, Otero MJ, Domínguez-Gil A, et al. Population pharmacokinetics of lamotrigine with data from therapeutic drug monitoring in German and Spanish patients with epilepsy. Ther Drug Monit. 2008;30:483–9.

    CAS  PubMed  Google Scholar 

  44. 44.

    Yamamoto Y, Takahashi Y, Imai K, Ikeda H, Takahashi M, Nakai M, et al. Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy. Drug Metab Pharmacokinet. 2015;30:214–20.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Inoue K, Yamamoto Y, Suzuki E, Takahashi T, Umemura A, Takahashi Y, et al. Factors that influence the pharmacokinetics of lamotrigine in Japanese patients with epilepsy. Eur J Clin Pharm. 2016;72:555–62.

    CAS  Article  Google Scholar 

  46. 46.

    Innocenti F, Ramírez J, Obel J, Xiong J, Mirkov S, Chiu YL, et al. Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751. Pharmacogenet Genom. 2013;23:374–81.

    CAS  Article  Google Scholar 

  47. 47.

    Liu W, Innocenti F, Ratain MJ. Linkage disequilibrium across the UGT1A locus should not be ignored in association studies of cancer susceptibility. Clin Cancer Res. 2005;11:1348–49.

    CAS  PubMed  Google Scholar 

  48. 48.

    Liu W, Ramírez J, Gamazon ER, Mirkov S, Chen P, Wu K, et al. Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver. Hum Mol Genet. 2014;23:5558–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Argikar UA, Remmel RP. Variation in glucuronidation of lamotrigine in human liver microsomes. Xenobiotica. 2009;39:355–63.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Saeki M, Saito Y, Jinno H, Tanaka-Kagawa T, Ohno A, Ozawa S, et al. Single nucleotide polymorphisms and haplotype frequencies of UGT2B4 and UGT2B7 in a Japanese population. Drug Metab Dispos. 2004;32:1048–54.

    CAS  PubMed  Google Scholar 

  51. 51.

    Fricke-Galindo I, Ortega-Vázquez A, Monroy-Jaramillo N, Dorado P, Jung-Cook H, Peñas-Lledó E, et al. Allele and genotype frequencies of genes relevant to anti-epileptic drug therapy in Mexican-Mestizo healthy volunteers. Pharmacogenomics. 2016;17:1913–30.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, et al. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genom. 2011;21:152–61.

    CAS  Article  Google Scholar 

  53. 53.

    Ortega-Vázquez A, Dorado P, Fricke-Galindo I, Jung-Cook H, Monroy-Jaramillo N, Martínez-Juárez IE, et al. CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy. Pharmacogenomics J. 2016;3:286–92.

    Article  CAS  Google Scholar 

  54. 54.

    Favela-Mendoza AF, Rangel-Villalobos H, Fricke-Galindo I, Ortega-Vázquez A, Martínez-Cortés G, López-López M. Genetic variability among Mexican Mestizo and Amerindian populations based on three ABCB1 polymorphisms. Mol Biol Rep. 2018;45:2525–33.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Seo T, Ishitsu T, Ueda N, Nakada N, Yurube K, Ueda K, et al. ABCB1 polymorphisms influence the response to antiepileptic drugs in Japanese epilepsy patients. Pharmacogenomics. 2006;7:551–61.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Ajmi M, Boujaafar S, Zouari N, Amor D, Nasr A, Rejeb NB, et al. Association between ABCB1 polymorphisms and response to first-generation antiepileptic drugs in a Tunisian epileptic population. Int J Neurosci. 2018;128:705–14.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Li SX, Liu YY, Wang QB. ABCB1 gene C3435T polymorphism and drug resistance in epilepsy: evidence based on 8,604 subjects. Med Sci Monit. 2015;21:861–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Sawyer MB, Innocenti F, Das S, Cheng C, Ramírez J, Pantle-Fisher FH, et al. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharm Ther. 2003;73:566–74.

    CAS  Article  Google Scholar 

  59. 59.

    Thibaudeau J, Lépine J, Tojcic J, Duguay Y, Pelletier G, Plante M, et al. Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone. Cancer Res. 2006;66:125–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology. 2007;132:272–81.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Duguay Y, Báár C, Skorpen F, Guillemette C. A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clin Pharm Ther. 2004;75:223–33.

    CAS  Article  Google Scholar 

  62. 62.

    National Center for Biotechnology Information. dbSNP. Available from: Accessed 2 May 2019.

  63. 63.

    Silva-Zolezzi I, Hidalgo-Miranda A, Estrada-Gil J, Fernandez-Lopez JC, Uribe-Figueroa L, Contreras A, et al. Analysis of genomic diversity in Mexican mestizo populations to develop genomic medicine in Mexico. Proc Natl Acad Sci USA. 2009;106:8611–6.

    CAS  PubMed  Article  Google Scholar 

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We are grateful for support from the Consejo Nacional de Ciencia y Tecnología (CONACYT) of Mexico grant #167261. This study was coordinated by RIBEF network (Red Iberoamericana de Farmacogenética y Farmacogenómica;

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Ortega-Vázquez, A., Fricke-Galindo, I., Dorado, P. et al. Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy. Pharmacogenomics J (2020).

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