Advertisement

International Journal of Clinical Pharmacy

, Volume 38, Issue 2, pp 388–394 | Cite as

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

  • Nazan Yuce-Artun
  • Bora Baskak
  • Erguvan Tugba Ozel-Kizil
  • Hatice Ozdemir
  • Zuhal Uckun
  • Halise Devrimci-Ozguven
  • Halit Sinan SuzenEmail author
Research Article

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.

Keywords

CYP2B6 CYP2C19 Cytochrome P450 Sertraline Pharmacogenetics 

Notes

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.

Conflicts of interest

The authors declare that they have no conflict of interest.

References

  1. 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.CrossRefPubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 3.
    Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286:487–91.CrossRefPubMedGoogle Scholar
  4. 4.
    Mrazek DA. Psychiatric pharmacogenomic testing in clinical practice. Dialogues Clin Neurosci. 2010;12:69–76.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009;48:689–723.CrossRefPubMedGoogle Scholar
  6. 6.
    Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part II. Clin Pharmacokinet. 2009;48:761–804.CrossRefPubMedGoogle Scholar
  7. 7.
    Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41:89–295.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.PubMedGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 16.
    Doogan DP, Caillard V. Sertraline in the prevention of depression. Br J Psychiatry. 1992;160:217–22.CrossRefPubMedGoogle Scholar
  17. 17.
    Doogan DP, Caillard V. Sertraline: a new antidepressant. J Clin Psychiatry. 1988;49(Suppl):46–51.PubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 19.
    Warrington SJ. Clinical implications of the pharmacology of sertraline. Int Clin Psychopharmacol. 1991;6:11–21.CrossRefPubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 22.
    Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI. Human cytochromes mediating sertraline biotransformation: seeking attribution. J Clin Psychopharmacol. 1999;19:489–93.CrossRefPubMedGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 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. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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. 34.
    Zanger UM, Klein K. Pharmacogenetics of cytochrome P450 2B6 [CYP2B6]: advances on polymorphisms, mechanisms, and clinical relevance. Front Genet. 2013;4:24.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 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.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Nazan Yuce-Artun
    • 1
  • Bora Baskak
    • 2
  • Erguvan Tugba Ozel-Kizil
    • 2
  • Hatice Ozdemir
    • 3
  • Zuhal Uckun
    • 4
  • Halise Devrimci-Ozguven
    • 5
  • Halit Sinan Suzen
    • 5
    Email author
  1. 1.Biotechnology InstituteAnkara UniversityAnkaraTurkey
  2. 2.School of Medicine, Psychiatry DepartmentAnkara UniversityAnkaraTurkey
  3. 3.School of Medicine, Psychiatry DepartmentKirikkale UniversityKirikkaleTurkey
  4. 4.Faculty of Pharmacy, Department of ToxicologyMersin UniversityMersinTurkey
  5. 5.Faculty of Pharmacy, Department of ToxicologyAnkara UniversityTandogan, AnkaraTurkey

Personalised recommendations