Skip to main content
SpringerLink
Log in

The Effect of Uridine Diphosphate Glucuronosyltransferase (UGT)1A6 Genetic Polymorphism on Valproic Acid Pharmacokinetics in Indian Patients with Epilepsy: A Pharmacogenetic Approach

  • Original Research Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Background and Objective

Sodium valproate is a widely prescribed broad-spectrum antiepileptic drug. It shows high inter-individual variability in pharmacokinetics and pharmacodynamics and has a narrow therapeutic range. We evaluated the effects of polymorphic uridine diphosphate glucuronosyltransferase (UGT)1A6 (541A>G, 552A>C) metabolizing enzyme on the pharmacokinetics of sodium valproate in the patients with epilepsy who showed toxicity to therapy.

Methods

Genotype analysis of the patients was made with polymerase chain–restriction fragment length polymorphism (RFLP) with sequencing. Plasma drug concentrations were measured with reversed phase high-performance liquid chromatography (HPLC) and concentration–time data were analyzed by using a non-compartmental approach.

Results

The results of this study suggested a significant genotypic as well as allelic association with valproic acid toxicity for UGT1A6 (541A>G) or UGT1A6 (552A>C) polymorphic enzymes. The elimination half-life (t ½ = 40.2 h) of valproic acid was longer and the clearance rate (CL = 917 ml/h) was lower in the poor metabolizers group of UGT1A6 (552A>C) polymorphism who showed toxicity than in the intermediate metabolizers group (t ½ = 35.5 h, CL = 1,022 ml/h) or the extensive metabolizers group (t ½ = 25.4 h, CL = 1,404 ml/h).

Conclusion

Our findings suggest that the UGT1A6 (552A>C) genetic polymorphism plays a significant role in the steady state concentration of valproic acid, and it thereby has an impact on the toxicity of the valproic acid used in the patients with epilepsy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kotsopoulos IA, Van Merode T, Kessels FG, Krom MC, Knottnerus JA. Systematic review and meta-analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia. 2002;43:1402–9.

    Article  PubMed  Google Scholar 

  2. Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry. 1996;61:433–43.

    Article  PubMed  CAS  Google Scholar 

  3. St Louis EK. Minimizing AED adverse effects: improving quality of life in the interictal state in epilepsy care. Curr Neuropharmacol. 2009;7:106–14.

    Article  PubMed  CAS  Google Scholar 

  4. Evans WE, McLeod HL. Pharmacogenomics, drug disposition, drug targets, and side effects. N Engl J Med. 2003;384:538.

    Google Scholar 

  5. Chadwick DW. Concentration-effect relationships of sodium valproate. Clin. Pharmacokinet. 1985;10:155–63.

    Article  PubMed  CAS  Google Scholar 

  6. Baillie TL, Sheffels PR. Valproate: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven Press; 1995. p. 589–604.

    Google Scholar 

  7. Burchell B, Brierley CH, Rance D. Specificity of human UDP-glucuronosyltransferases and xenobiotic glucuronidation. Life Sci. 1995;57:1819–31.

    Article  PubMed  CAS  Google Scholar 

  8. King CD, Rios GR, Green MD, Tephly TR. UDP-glucuronosyltransferases. Curr Drug Metab. 2000;1:143–61.

    Article  PubMed  CAS  Google Scholar 

  9. Burchell B, Brierley CH, Monaghan G. The structure and function of the UDP-glucuronosyltransferase gene family. Adv Pharmacol. 1998;42:335–8.

    Article  PubMed  CAS  Google Scholar 

  10. Mackenzie PI, Owens IS, Burchell B. The UDP-glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics. 1997;7:255–69.

    Article  PubMed  CAS  Google Scholar 

  11. Orzechowski A, Schrenk D, Bock-Hennig BS, Bock KW. Glucuronidation of carcinogenic arylamines and their N-hydroxy derivatives by rat and human phenol UDP-glucuronosyltransferase of the UGT1 gene complex. Carcinogenesis. 1994;15:1549–53.

    Article  PubMed  CAS  Google Scholar 

  12. Woosterk R, Sutherland L, Ebner T, Clarke D, Da Cruz e Silva O, Burchell B. Cloning and stable expression of a new member of the human liver phenol/ bilirubin: UDP-glucuronosyltransferase cDNA family. Biochem J. 1991;278:465–9.

    Google Scholar 

  13. Ciotti M, Marrone A, Potter C, Owens IS. Genetic polymorphism in the human UGT1A6 UDP-glucuronosyltransferase: pharmacological implications. Pharmacogenetics. 1997;7:485–95.

    Article  PubMed  CAS  Google Scholar 

  14. Krishnaswamy S, Hao Q, Al-Rohaimi A. UDP glucuronosyltransferase (UGT)1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther. 2005;313:1340–6.

    Article  PubMed  CAS  Google Scholar 

  15. Comey CT, Koons BW, Presley KW, Smerick JB, Sobieralski CA, Stanley DM. DNA extraction strategies for amplified fragment length polymorphism analysis. J Forensic Sci. 1994;39:1254–69.

    CAS  Google Scholar 

  16. Verlaan M, Morsche RH, Pap A, et al. Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis. Pharmacogenetics. 2004;14:351–7.

    Article  PubMed  CAS  Google Scholar 

  17. Amini H, Javan M, Ahmadiani A. Development and validation of a sensitive assay of valproic acid in human plasma by high-performance liquid chromatography without prior derivatization. J Chromatogr B Analyt Technol Biomed Life Sci. 2006;830:368–71.

    Article  PubMed  CAS  Google Scholar 

  18. Kishore P, Rajani Kumar V, Satyanarayana V, Krishna DR. HPLC determination of valproic acid in human serum. Pharmazie. 2003;58:378–80.

    PubMed  CAS  Google Scholar 

  19. Ketter TA, Frye MA, Cora-Locatelli G, Kimbrell TA. Metabolism and excretion of mood stabilizers and new anticonvulsants. Cell Mol Neurobiol. 1999;19:511–32.

    Article  PubMed  CAS  Google Scholar 

  20. Nagar S, Zalatoris JJ, Blanchard RL. Human UGT 1A6 pharmacogenetics: identification of a novel SNP, characterization of allele frequencies and functional analysis of recombinant allozymes in human liver tissue and in cultured cells. Pharmacogenetics. 2004;14:487–99.

    Article  PubMed  CAS  Google Scholar 

  21. Lampe JW, Bigler J, Horner NK, Potter JD. UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum Bilirubin concentrations. Pharmacogenetics. 1999;9:341–9.

    Article  PubMed  CAS  Google Scholar 

  22. Zaccara G, Messori A, Moroni F. Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet. 1998;15:367–89.

    Article  Google Scholar 

  23. Park HM, Kang SS, Lee YB, Shin DJ, Kim ON, Lee SB, et al. Population pharmacokinetics of intravenous valproic acid in Korean patients. J Clin Pharm Ther. 2002;27:419–25.

    Article  PubMed  CAS  Google Scholar 

  24. Levy RH, Mattson RH, Meldrum BS, Perucca E. Antiepileptic drugs. 5th ed. New York: Raven Press; 2002.

    Google Scholar 

  25. Schobben F, van Der Kleijn E, Gabreels JM. Pharmacokinetics of di-n-propylacetate in epileptic patients. Eur J Clin Pharmacol. 1975;8:97–105.

    Article  PubMed  CAS  Google Scholar 

  26. Chu XM, Zhang LF, Wang GJ, Zhang SN, Zhou JH, Hao HP. Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients. Eur J Clin Pharmacol. 2012;68:1395–401.

    Article  PubMed  CAS  Google Scholar 

  27. Wang Y, Gao L, Liu YP, Huang NN, Xu SJ, Ma DJ. Effect of UGTIA6 A541G genetic polymorphism on the metabolism of valproic acid in Han epileptic children from Henan. Zhongguo Dang Dai Er Ke Za Zhi. 2010;12:429–32.

    PubMed  Google Scholar 

Download references

Acknowledgments

The work was supported by the Department of Biotechnology (DBT), Ministry of Science and Technology, New Delhi, and we thank Issam Hamadeh, Pharm D, University of Florida, Gainesville for his valuable suggestions on the manuscript.

Conflicts of Interest

The authors have no conflicts of interest that are directly relevant to the content of this article.

Author information

Authors and Affiliations

  1. Department of Neurobiochemistry, Neurosciences Center, All India Institute of Medical Sciences, New Delhi, 110029, India

    Murali Munisamy & Vivekanandhan Subbiah

  2. Department of Neurology, AIIMS, New Delhi, India

    Manjari Tripathi & Madhuri Behari

  3. Department of Neurology, Safdarjung Hospital, New Delhi, India

    S. Raghavan, D. C. Jain & Barghavi Ramanujam

  4. Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India

    Karthik Arumugam, Thiyagu Rajakannan & Surulivel Rajan Mallayasamy

Authors
  1. Murali Munisamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manjari Tripathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Madhuri Behari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Raghavan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. C. Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Barghavi Ramanujam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Karthik Arumugam
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thiyagu Rajakannan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Surulivel Rajan Mallayasamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vivekanandhan Subbiah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vivekanandhan Subbiah.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Munisamy, M., Tripathi, M., Behari, M. et al. The Effect of Uridine Diphosphate Glucuronosyltransferase (UGT)1A6 Genetic Polymorphism on Valproic Acid Pharmacokinetics in Indian Patients with Epilepsy: A Pharmacogenetic Approach. Mol Diagn Ther 17, 319–326 (2013). https://doi.org/10.1007/s40291-013-0041-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-013-0041-8

Keywords

Search

Navigation