Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients

Pharmacogenetics

Abstract

Objective

To investigate the impact of CYP2C19 genotype on serum concentrations of sertraline and N-desmethyl sertraline in psychiatric patients.

Methods

Patients treated with sertraline (n = 121) were divided into six subgroups according to CYP2C19 genotype: CYP2C19*17/*17, CYP2C19*1/*17, CYP2C19*1/*1, CYP2C19*17/def, CYP2C19*1/def and CYP2C19def/def (def = allele encoding defective CYP2C19 metabolism, i.e. *2 and *3). Dose-adjusted serum concentrations were compared by linear mixed model analyses using the CYP2C19*1/*1 subgroup as reference.

Results

Subgroups carrying one or two alleles encoding defective CYP2C19 metabolism achieved significantly higher mean dose-adjusted serum concentrations of sertraline and N-desmethyl sertraline compared to the CYP2C19*1/*1 subgroup (P < 0.05). The effect of CYP2C19 genotype was expressed as 3.2-fold (sertraline) and 4.5-fold (N-desmethyl sertraline) higher dose-adjusted serum concentrations in the CYP2C19def/def subgroup compared to the CYP2C19*1/*1 subgroup (P < 0.01). The CYP2C19*17 allele had no influence on the dose-adjusted serum concentrations of sertraline and N-desmethyl sertraline.

Conclusion

The significantly higher serum concentrations associated with alleles encoding defective CYP2C19 metabolism might be of relevance for the clinical outcome of sertraline treatment.

Keywords

CYP2C19 CYP2C19*17 Genotype Sertraline N-desmethyl sertraline 

Notes

Acknowledgements

The authors thank Marianne Hjerpset, Lene Kristin Støten and Linda Uthus for performing the serum analyses and the genotyping.

References

  1. 1.
    Wilkinson GR (2005) Drug metabolism and variability among patients in drug response. N Engl J Med 352:2211–2221PubMedCrossRefGoogle Scholar
  2. 2.
    Desta Z, Zhao X, Shin JG, Flockhart DA (2002) Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41:913–958PubMedCrossRefGoogle Scholar
  3. 3.
    Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM (2004) The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol 199:193–209PubMedCrossRefGoogle Scholar
  4. 4.
    Human Cytochrome P450 Allele Nomenclature Committee CYP2C19 allele nomenclature. http://www.cypalleles.ki.se/cyp2C19.htm Accessed May 2008
  5. 5.
    Sim SC, Risinger C, Dahl ML et al (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79:103–113PubMedCrossRefGoogle Scholar
  6. 6.
    Morinobu S, Tanaka T, Kawakatsu S et al (1997) Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy. Psychiatry Clin Neurosci 51:253–257PubMedCrossRefGoogle Scholar
  7. 7.
    Koyama E, Tanaka T, Chiba K et al (1996) Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4′-hydroxylation status in Japanese depressive patients. J Clin Psychopharmacol 16:286–293PubMedCrossRefGoogle Scholar
  8. 8.
    Kirchheiner J, Muller G, Meineke I et al (2003) Effects of polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics. J Clin Psychopharmacol 23:459–466PubMedCrossRefGoogle Scholar
  9. 9.
    Nielsen KK, Brosen K, Hansen MG, Gram LF (1994) Single-dose kinetics of clomipramine: relationship to the sparteine and S-mephenytoin oxidation polymorphisms. Clin Pharmacol Ther 55:518–527PubMedGoogle Scholar
  10. 10.
    Jiang ZP, Shu Y, Chen XP et al (2002) The role of CYP2C19 in amitriptyline N-demethylation in Chinese subjects. Eur J Clin Pharmacol 58:109–113PubMedCrossRefGoogle Scholar
  11. 11.
    Sindrup SH, Brosen K, Hansen MG et al (1993) Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 15:11–17PubMedCrossRefGoogle Scholar
  12. 12.
    Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E (2008) Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther 83:322–327PubMedCrossRefGoogle Scholar
  13. 13.
    Wang JH, Liu ZQ, Wang W et al (2001) Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19. Clin Pharmacol Ther 70:42–47PubMedCrossRefGoogle Scholar
  14. 14.
    Liu ZQ, Cheng ZN, Huang SL et al (2001) Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects. Br J Clin Pharmacol 52:96–99PubMedCrossRefGoogle Scholar
  15. 15.
    Yu KS, Yim DS, Cho JY et al (2001) Effect of omeprazole on the pharmacokinetics of moclobemide according to the genetic polymorphism of CYP2C19. Clin Pharmacol Ther 69:266–273PubMedCrossRefGoogle Scholar
  16. 16.
    Gram LF, Guentert TW, Grange S, Vistisen K, Brosen K (1995) Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: a panel study. Clin Pharmacol Ther 57:670–677PubMedCrossRefGoogle Scholar
  17. 17.
    Norwegian Institute of Public Health, Department of Pharmacoepidemiology (2008) Drug Consumption in Norway 2003–2007. http://www.legemiddelforbruk.no/english/. Accessed May 2008
  18. 18.
    Kobayashi K, Ishizuka T, Shimada N et al (1999) Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metab Dispos 27:763–766PubMedGoogle Scholar
  19. 19.
    Obach RS, Cox LM, Tremaine LM (2005) Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos 33:262–270PubMedCrossRefGoogle Scholar
  20. 20.
    Xu ZH, Wang W, Zhao XJ et al (1999) Evidence for involvement of polymorphic CYP2C19 and 2C9 in the N-demethylation of sertraline in human liver microsomes. Br J Clin Pharmacol 48:416–423PubMedCrossRefGoogle Scholar
  21. 21.
    Baumann P, Hiemke C, Ulrich S et al (2004) The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 37:243–265PubMedCrossRefGoogle Scholar
  22. 22.
    Koe BK, Weissman A, Welch WM, Browne RG (1983) Sertraline, 1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin. J Pharmacol Exp Ther 226:686–700PubMedGoogle Scholar
  23. 23.
    Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (1997) Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 283:1305–1322PubMedGoogle Scholar
  24. 24.
    Bolden-Watson C, Richelson E (1993) Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes. Life Sci 52:1023–1029PubMedCrossRefGoogle Scholar
  25. 25.
    Indiana University School of Medicine (2008) Drug interactions. Cytochrome P450 system. http://medicine.iupui.edu/flockhart/. Accessed Feb 2008
  26. 26.
    www.cyp450.no (2008) Cytochrome P450. www.CYP450.no. Accessed Feb 2008
  27. 27.
    Lovlie R, Daly AK, Molven A, Idle JR, Steen VM (1996) Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene. FEBS Lett 392:30–34PubMedCrossRefGoogle Scholar
  28. 28.
    Steen VM, Andreassen OA, Daly AK et al (1995) Detection of the poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology. Pharmacogenetics 5:215–223PubMedCrossRefGoogle Scholar
  29. 29.
    Altman DG (1999) Practical statistics for medical research. Chapman & Hall/CRC, Boca Raton, pp 229–276Google Scholar
  30. 30.
    Walton R, Kimber M, Rockett K (2005) Haplotype block structure of the cytochrome P450 CYP2C gene cluster on chromosome 10. Nat Genet 37:915–916PubMedCrossRefGoogle Scholar
  31. 31.
    Baldwin RM, Ohlsson S, Pedersen RS et al (2008) Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. Br J Clin Pharmacol 65:767–74PubMedCrossRefGoogle Scholar
  32. 32.
    Mauri MC, Laini V, Cerveri G et al (2002) Clinical outcome and tolerability of sertraline in major depression: a study with plasma levels. Prog Neuro-psychopharmacol Biol Psychiatry 26:597–601CrossRefGoogle Scholar
  33. 33.
    Suzuki Y, Fukui N, Sawamura K et al (2008) Concentration-response relationship for fluvoxamine using remission as an endpoint: a receiver operating characteristics curve analysis in major depression. J Clin Psychopharmacol 28:325–328PubMedCrossRefGoogle Scholar
  34. 34.
    Klotz U, Schwab M, Treiber G (2004) CYP2C19 polymorphism and proton pump inhibitors. Basic Clin Pharmacol Toxicol 95:2–8PubMedGoogle Scholar
  35. 35.
    Bebia Z, Buch SC, Wilson JW et al (2004) Bioequivalence revisited: influence of age and sex on CYP enzymes. Clin Pharmacol Ther 76:618–627PubMedCrossRefGoogle Scholar
  36. 36.
    Hamelin BA, Turgeon J, Vallee F et al (1993) The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin. Clin Pharmacol Ther 60:512–521CrossRefGoogle Scholar
  37. 37.
    Xie HG, Stein CM, Kim RB et al (1999) Allelic, genotypic and phenotypic distributions of S-mephenytoin 4′-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 9:539–549PubMedCrossRefGoogle Scholar
  38. 38.
    Kurzawski M, Gawronska-Szklarz B, Wrzesniewska J et al (2006) Effect of CYP2C19*17 gene variant on Helicobacter pylori eradication in peptic ulcer patients. Eur J Clin Pharmacol 62:877–880PubMedCrossRefGoogle Scholar
  39. 39.
    Ozdemir V, Williams-Jones B, Cooper DM, Someya T, Godard B (2007) Mapping translational research in personalized therapeutics: from molecular markers to health policy. Pharmacogenomics 8:177–185PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of PsychopharmacologyDiakonhjemmet HospitalOsloNorway
  2. 2.Department of Pharmaceutical Biosciences, School of PharmacyUniversity of OsloOsloNorway

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