The pharmacogenomics of lamotrigine (a literature review)

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Abstract

Pharmacogenomics aims to optimize drug therapy with respect to genetic variations in various human genes, whose products affect drug pharmacokinetics and pharmacodynamics. Among neurological diseases, selecting effective drug therapy is especially important in epilepsy since recurrent epileptic seizures can lead to persistent epileptic brain activity and patient traumatization.

Lamotrigine is a new generation broad-spectrum antiepileptic drug and is recommended as the drug of choice in focal and generalized epilepsy. By genotyping single-nucleotide polymorphisms (SNPs) associated with decreased or increased lamotrigine blood concentration, predicting the drug dose that will achieve the therapeutic serum concentration is possible. Selecting an appropriate individual drug dose avoids the development of dose-dependent side effects, which occur when the serum drug concentration is exceeded and drug discontinuation due to a lack of the expected effect because of insufficient blood levels.

This review presents the results of studies of the polymorphism in genes that directly or indirectly alter lamotrigine serum levels. These include genes that encode the UGT enzymes, responsible for the conjugation and elimination of lamotrigine from the body; genes that encode transport proteins (P-glycoprotein, organic cation transporter, multidrug resistance protein, and breast cancer resistance protein); genes that encode the transcription factors HNF4α and pregnane X receptor, which regulate the expression of several liver transport proteins and enzymes. The reviewed data demonstrate the relationship between polymorphisms in these genes and changes in lamotrigine concentration.

About the authors

Asya M. Azhigova

Moscow State University of Medicine and Dentistry

Author for correspondence.
Email: asjotr@mail.ru
Russian Federation, Moscow

Amayak G. Broutian

Research Center of Neurology

Email: asjotr@mail.ru
Russian Federation, Moscow

Pavel N. Vlasov

Moscow State University of Medicine and Dentistry

Email: asjotr@mail.ru
Russian Federation, Moscow

References

  1. Vogel F. Moderne probleme der Humangenetik. Ergeb Inn Med Kinderheilkd. 1959; 12: 52–125.
  2. Lander E.S., Linton L.M., Birren B. et al. Initial sequencing and analysis of the human genome. Nature. 2001; 409(6822):860-921. doi: 10.1038/35057062. PMID: 11237011.
  3. Venter J.C., Adams M.D., Myers E.W. et al. The sequence of the human genome. Science. 2001; 291(5507):1304-51. doi: 10.1126/science.1058040. PMID: 11181995.
  4. Brodie M.J., Barry S.J.E., Bamagous G.A. et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012; 78(20): 1548–1554. doi: 10.1212/WNL.0b013e3182563b19. PMID: 22573629.
  5. Cohen A.F., Land G.S., Breimer D.D. et al. Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans. Clin Pharmacol Ther. 1987; 42(5): 535–541. doi: 10.1038/clpt.1987.193. PMID: 3677542.
  6. Rambeck B., Wolf P. Lamotrigine clinical pharmacokinetics. Clin Pharmacokinet. 1993; 25(6): 433–443. doi: 10.2165/00003088-199325060-00003. PMID: 8119045.
  7. Belousov D.Yu. [Side effects of second generation antiepileptic drugs].Kachestvennaya klinicheskaya praktika. 2008; (2): 79–81
  8. Hirsch L.J., Weintraub D., Du Y. et al. Correlating lamotrigine serum concentrations with tolerability in patients with epilepsy. Neurology. 2004; 63(6): 1022–1026. doi: 10.1212/01.WNL.0000138424.33979.0c. PMID: 15452293.
  9. 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 Pharmacol. 2013; 69(6): 1285–1291. doi: 10.1007/s00228-012-1449-5. PMID: 23263737.
  10. Milosheska D., Lorber B., Vovk T. et al. Pharmacokinetics of lamotrigine and Its metabolite N-2-glucuronide: influence of polymorphism of UDP-glucuronosyltransferases and drug transporters. Br J Clin Pharmacol. 2016; 82(2): 399–411. doi: 10.1111/bcp.12984. PMID: 27096250.
  11. Sánchez B., Herranz J.L., Leno C. et al. UGT2B7-161C>T polymorphism is associated with lamotrigine concentration-to-dose ratio in a multivariate study. Ther Drug Monitor. 2010; 32(2): 177–84. doi: 10.1097/FTD.0b013e3181ceecc6. PMID: 20216122.
  12. Inoue K., Yamamoto Y., Suzuki E. et al. Factors that influence the pharmacokinetics of lamotrigine in Japanese patients with epilepsy. Eur J Clin Pharmacol. 2016; 72(5): 555–562. doi: 10.1007/s00228-016-2008-2. PMID: 26790665.
  13. Reimers A., Sjursen W., Helde G. et al. Frequencies of UGT1A4∗2 (P24T) and∗3 (L48V) and their effects on serum concentrations of lamotrigine. Eur J Drug Metab Pharmacokinet. 2016; 41(2): 149–155. doi: 10.1007/s13318-014-0247-0. PMID: 25492569.
  14. Ozkaynakci A., Gulcebi M.I., Ergec D. et al. The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy. Epilepsy Res. 2011; 95(1–2): 1–8. doi: 10.1016/j.eplepsyres.2011.01.016. PMID: 21601426.
  15. Zhou J., Argikar U., Remmel R. Functional analysis of UGT1A4 P24T and UGT1A4 L48V variant enzymes. Pharmacogenomics. 2011; 12(12): 1671–1679. doi: 10.2217/pgs.11.105. PMID: 22047493.
  16. Chang Y., Yang L.Y., Zhang M., Liu S. Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China. Eur J Clin Pharmacol. 2014; 70(8): 941–946. doi: 10.1007/s00228-014-1690-1. PMID: 24820767.
  17. Provenzani A., Labbozzetta M., Notarbartolo M. et al. Rash and multiorgan dysfunction following lamotrigine: could genetic be involved? Int J Clin Pharm. 2015; 37(5): 682–686. doi: 10.1007/s11096-015-0158-4. PMID: 26173940.
  18. Domjanović I.K., Lovric M., Trkulja V. et al. Interaction between ABCG2 421C>A polymorphism and valproate in their effects on steady-state disposition of lamotrigine in adults with epilepsy. Nucleus. 2018; 84(9): 2106–2119. doi: 10.1080/19491034.2018.1462635. PMID: 29791014.
  19. Wang Z., Zhang Y., Huang W. et al. Effects of comedication and genetic factors on the population pharmacokinetics of lamotrigine: a prospective analysis in Chinese patients with epilepsy. Front Pharmacol. 2019. 10: 832. doi: 10.3389/fphar.2019.00832. PMID: 31404235.
  20. Suzuki T., Mihara K., Nagai G. et al. Relationship between UGT1A4 and UGT2B7 polymorphisms and the steady-state plasma concentrations of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy. Ther Drug Monit. 2019; 41(1): 86–90. doi: 10.1097/FTD.0000000000000577. PMID: 30489548.
  21. Dickens D., Owen A., Alfirevic A. et al. Lamotrigine is a substrate for OCT1 in brain endothelial cells. Biochem Pharmacol. 2012; 83(6): 805–814. doi: 10.1016/j.bcp.2011.12.032. PMID: 22227272.
  22. Shen C.H., Zhang Y.X., Lu R.Y. et al. Specific OCT1 and ABCG2 polymorphisms are associated with lamotrigine concentrations in chinese patients with epilepsy. Epilepsy Res. 2016; 127: 186–190. doi: 10.1016/j.eplepsyres.2016.09.004. PMID: 27610747.
  23. Grant M.J. The Genetic Determinants of Lamotrigine Dosing in Epilepsy. Liverpool, 2010.
  24. Zhou Y., Wang X., Li H. et al. Polymorphisms of ABCG2, ABCB1 and HNF4α are associated with lamotrigine trough concentrations in epilepsy patients. Drug Metab Pharmacokinet. 2015; 30(4): 282–287. doi: 10.1016/j.dmpk.2015.05.002. PMID: 26213157.
  25. Lovrić M., Božina N.,Hajnsek S. et al. Association between lamotrigine concentrations and ABCB1 polymorphisms in patients with epilepsy. Ther Drug Monit. 2012; 34(5): 518–525. doi: 10.1097/FTD.0b013e31826517c6. PMID: 22972536.

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Copyright (c) 2021 Azhigova A.M., Broutian A.G., Vlasov P.N.

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