Skip to main content
SpringerLink
Log in

Influence of CYP2B6 and CYP2C19 polymorphisms on sertraline metabolism in major depression patients

  • Research Article
  • Published:
International Journal of Clinical Pharmacy Aims and scope Submit manuscript

Abstract

Background Genetic polymorphisms in CYP2B6 and CYP2C19 may cause variability in the metabolism of sertraline, a widely used antidepressant in major depressive disorder treatment. Objective This study investigates the impact of CYP2B6*4 (785A > G), CYP2B6*9 (516G > T), CYP2B6*6 (516G > T + 685G > A) CYP2C19*2 (685G > A), CYP2C19*17 (−3402C > T) polymorphisms on plasma concentrations of sertraline and N-desmethyl sertraline in major depression patients treated with sertraline [n = 50]. Setting Participants were patients who admitted to an adult psychiatry outpatient unit at a university hospital. These were DSM-IV major depression diagnosed patients with a stable sertraline medication regimen [for at least one month]. Methods CYP2B6*4 (rs 2279343; 785A > G), CYP2B6*9 (516G > T; rs 3745274), CYP2B6*6 (516G > T + 685G > A) CYP2C19*2 (rs 4244285; 685G > A), CYP2C19*17 (rs 11188072; −3402C > T), polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Plasma concentrations were measured by high-performance liquid chromatography in patients treated with SERT. Main outcome measure The distribution of CYP2B6*4, *6, *9 and CYP2C19*2, *17 among patient group and the association between genotype and sertraline metabolism. Results Sertraline, N-desmethyl sertraline, N-desmethyl sertraline/sertraline and dose-adjusted plasma concentrations were statistically compared between individuals with wild-type and variant alleles both for CYP2B6 and CYP2C19 enzymes. The mean N-desmethyl sertraline/sertraline value, was significantly lower in all subgroups with *6 and *9 variant alleles (p < 0.05). Sertraline/C values were significantly higher (p <  0.05) and N-desmethyl sertraline/C values were lower in all subgroups with *6 and *9 variant alleles compared to wild-type subgroup. Conclusion CYP2B6*6 and *9 variant alleles had a significant decreasing effect on sertraline metabolism in major depression patients which might result as variations in sertraline therapy.

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

Similar content being viewed by others

References

  1. Mauri MC, Fiorentini A, Cerveri G, Volonteri LS, Regispani F, Malvini L, et al. Long-term efficacy and therapeutic drug monitoring of sertraline in major depression. Hum Psychopharmacol. 2003;18:385–8.

    Article  CAS  PubMed  Google Scholar 

  2. de Leon J. Incorporating pharmacogenetics into clinical practice: reality of a new tool in psychiatry. Current issues in clinical implementation. CNS Spectr. 2006;11(Suppl 3):8–12.

    PubMed  Google Scholar 

  3. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286:487–91.

    Article  CAS  PubMed  Google Scholar 

  4. Mrazek DA. Psychiatric pharmacogenomic testing in clinical practice. Dialogues Clin Neurosci. 2010;12:69–76.

    PubMed  PubMed Central  Google Scholar 

  5. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009;48:689–723.

    Article  CAS  PubMed  Google Scholar 

  6. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part II. Clin Pharmacokinet. 2009;48:761–804.

    Article  CAS  PubMed  Google Scholar 

  7. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41:89–295.

    Article  CAS  PubMed  Google Scholar 

  8. Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, Egberts K, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44:195–235.

    Article  Google Scholar 

  9. Murdoch D, McTavish D. Sertraline: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depression and obsessive compulsive disorder. Drugs. 1992;44:604–24.

    Article  CAS  PubMed  Google Scholar 

  10. Chouinard G, Goodman W, Greist J, Jenike M, Rasmussen S, White K, et al. Results of a double-blind, placebo-controlled trial of a new serotonin uptake inhibitor, sertraline, in the treatment of obsessive compulsive disorder. Psychopharmacol Bull. 1990;26:279–84.

    CAS  PubMed  Google Scholar 

  11. Cohn CK, Shrivestava R, Mendels J, Cohn JB, Fabre LF, Claghorn JL, et al. Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients. J Clin Psychiatry. 1990;51(Suppl B):28–33.

    PubMed  Google Scholar 

  12. Greist J, Chouinard G, DuBoff E, Halaris A, Kim SW, Koran L, et al. Double-blind, parallel comparison of three dosages of sertraline and placebo in outpatients with obsessive-compulsive disorder. Arch Gen Psychiatry. 1995;52:289–95.

    Article  CAS  PubMed  Google Scholar 

  13. Greist JH, Jefferson JW, Kobak KA, Chouinard G, DuBoff E, Halaris A, et al. A 1-year double-blind, placebo-controlled, fixed-dose study of sertraline in the treatment of obsessive-compulsive disorder. Int Clin Psychopharmacol. 1995;10:57–65.

    Article  CAS  PubMed  Google Scholar 

  14. Reimherr FW, Chouinard G, Cohn CK, Cole JO, Itil TM, LaPierre YD, et al. Antidepressant efficacy of sertraline: a double-blind, placebo and amitriptyline-controlled, multicenter comparison study in outpatients with major depression. J Clin Psychiatry. 1990;51(Suppl B):18–27.

    PubMed  Google Scholar 

  15. Fabre LF, Abuzzahab FS, Amin M, Claghorn JL, Mendels J, Petrie WM, et al. Sertraline safety and efficacy in major depression: a double-blind, fixed-dose comparison with placebo. Biol Psychiatry. 1995;38:592–602.

    Article  CAS  PubMed  Google Scholar 

  16. Doogan DP, Caillard V. Sertraline in the prevention of depression. Br J Psychiatry. 1992;160:217–22.

    Article  CAS  PubMed  Google Scholar 

  17. Doogan DP, Caillard V. Sertraline: a new antidepressant. J Clin Psychiatry. 1988;49(Suppl):46–51.

    PubMed  Google Scholar 

  18. Lundmark J, Bengtsson F, Nordin C, et al. Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients. Acta Psychiatr Scand. 2000;101:354–9.

    Article  CAS  PubMed  Google Scholar 

  19. Warrington SJ. Clinical implications of the pharmacology of sertraline. Int Clin Psychopharmacol. 1991;6:11–21.

    Article  PubMed  Google Scholar 

  20. Reis M, Aberg-Wistedt A, Agren H, Höglund P, Akerblad AC, Bengtsson F. Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression. Hum Psychopharmacol. 2004;19:283–91.

    Article  CAS  PubMed  Google Scholar 

  21. Reis M, Aamo T, Spigset O, Ahlner J. Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database. Ther Drug Monit. 2009;31:42–56.

    Article  CAS  PubMed  Google Scholar 

  22. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI. Human cytochromes mediating sertraline biotransformation: seeking attribution. J Clin Psychopharmacol. 1999;19:489–93.

    Article  CAS  PubMed  Google Scholar 

  23. Kobayashi K, Ishizuka T, Shimada N, Yoshimura Y, Kamijima K, Chiba K. Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metab Dispos. 1999;27:763–6.

    CAS  PubMed  Google Scholar 

  24. Xu ZH, Wang W, Zhao XJ, Huang SL, Zhu B, He N, et al. Evidence for involvement of polymorphic CYP2C19 and 2C9 in the N demethylation of sertraline in human liver microsomes. Br J Clin Pharmacol. 1999;48:416–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Obach RS, Cox LM, Tremaine LM. Sertraline a P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos. 2005;33:262–70.

    Article  CAS  PubMed  Google Scholar 

  26. Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics. 2007;8:743–59.

    Article  CAS  PubMed  Google Scholar 

  27. Lang T, Klein K, Fisher J, et al. Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics. 2001;11:399–415.

    Article  CAS  PubMed  Google Scholar 

  28. de Morais SMF, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA. Identification of a new genetic defect responsible for the polymorphism of S-mephenytoin metabolism in Japanese. Mol Pharmacol. 1994;46:594–8.

    PubMed  Google Scholar 

  29. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther. 2006;79(1):103–13.

    Article  CAS  PubMed  Google Scholar 

  30. First MB, Spitzer RL, Gibbon M, et al. Structured clinical interview for DSM-IV clinical version [SCID-I/CV]. American Psychiatric Pres: Washington DC; 1997.

    Google Scholar 

  31. Pang YS, Wong LP, Lee TC, Mustafa AM, Mohamed Z, Lang CC. Genetic polymorphism of cytochrome P450 2C19 in healthy Malaysian subjects. Br J Clin Pharmacol. 2004;58(3):332–5.

    Article  CAS  PubMed  Google Scholar 

  32. Yuce-Artun N, Kose G, Suzen HS. Allele and genotype frequencies of CYP2B6 in a Turkish population. Mol Biol Rep. 2014;41(6):3891–6.

    Article  CAS  PubMed  Google Scholar 

  33. Yuce-Artun N, Ozel Kizil ET, Baskak B, Devrimci Ozguven H, Duydu Y, Suzen HS. Determination of sertraline and its metabolite by high-pressure liquid chromatography in plasma. Rev Roum Chim. 2015;60(5–6):543–8.

    Google Scholar 

  34. Zanger UM, Klein K. Pharmacogenetics of cytochrome P450 2B6 [CYP2B6]: advances on polymorphisms, mechanisms, and clinical relevance. Front Genet. 2013;4:24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Klein K, Lang T, Saussele T, et al. Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet Genom. 2005;15(12):861–73.

    Article  CAS  Google Scholar 

  36. Cho JY, Lim HS, Chung JY, et al. Haplotype structure and allele frequencies of CYP2B6 in a Korean population. Drug Metab Dispos. 2004;32:1341–4.

    Article  CAS  PubMed  Google Scholar 

  37. Mehlotra RK, Ziats MN, Bockarie MJ, Zimmerman PA. Prevalence of CYP2B6 alleles in malaria endemic populations of West Africa and Papua New Guinea. Eur J Clin Pharmacol. 2006;62:267–75.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hofmann MH, Blievernicht JK, Klien K, Saussele T, Schaeffeler E, Schwab M, et al. Aberrant splicing caused by single nucleotide polymorphism c.516G > T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CY2B6 in liver. J Pharmacol Exp Ther. 2008;325:284–92.

    Article  CAS  PubMed  Google Scholar 

  39. Rudberg I, Hermann M, Refsum H. Molden E Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients. Eur J Clin Pharmacol. 2008;64:1181–8.

    Article  CAS  PubMed  Google Scholar 

  40. Aynacioglu AS, Sachse C, Bozkurt A, Kortunay S, Nacak M, Schröder T, et al. Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population. Clin Pharmacol Ther. 1999;66:185–92.

    Article  CAS  PubMed  Google Scholar 

  41. Uckun Z, Baskak B, Ozel-Kizil ET, Ozdemir H, Devrimci Ozguven H, Suzen HS. The impact of CYP2C19 polymorphisms on citalopram metabolism in patients with major depressive disorder. J Clin Pharm Ther. 2015;40:672–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge nurses for the skilled assistance during blood collection in the psychiatry departments.

Funding

This work was supported by The Scientific and Technological Research Council of Turkey under Project 109S147.

Author information

Authors and Affiliations

  1. Biotechnology Institute, Ankara University, Ankara, Turkey

    Nazan Yuce-Artun

  2. School of Medicine, Psychiatry Department, Ankara University, Dikimevi, Ankara, Turkey

    Bora Baskak & Erguvan Tugba Ozel-Kizil

  3. School of Medicine, Psychiatry Department, Kirikkale University, Kirikkale, Turkey

    Hatice Ozdemir

  4. Faculty of Pharmacy, Department of Toxicology, Mersin University, Mersin, Turkey

    Zuhal Uckun

  5. Faculty of Pharmacy, Department of Toxicology, Ankara University, Tandogan, Ankara, Turkey

    Halise Devrimci-Ozguven & Halit Sinan Suzen

Authors
  1. Nazan Yuce-Artun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bora Baskak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erguvan Tugba Ozel-Kizil
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hatice Ozdemir
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zuhal Uckun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Halise Devrimci-Ozguven
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Halit Sinan Suzen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Halit Sinan Suzen.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yuce-Artun, N., Baskak, B., Ozel-Kizil, E.T. et al. Influence of CYP2B6 and CYP2C19 polymorphisms on sertraline metabolism in major depression patients. Int J Clin Pharm 38, 388–394 (2016). https://doi.org/10.1007/s11096-016-0259-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11096-016-0259-8

Keywords

Search

Navigation