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The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

Abstract

CYP2C19 converts the tricyclic antidepressant imipramine to its active metabolite desipramine, which is subsequently inactivated by CYP2D6. The novel CYP2C19*17 allele causes ultrarapid metabolism of CYP2C19 substrates. We genotyped 178 depressed patients on imipramine for CYP2C19*17, and measured steady-state imipramine and desipramine plasma concentrations. Mean dose-corrected imipramine plasma concentration was significantly dependent on CYP2C19 genotype (Kruskal–Wallis test, P=0.01), with circa 30% lower levels in CYP2C19*17/*17 individuals compared with CYP2C19*1/*1 (wild-type) patients. The mean dose-corrected imipramine+desipramine plasma concentrations and imipramine/desipramine ratios were not significantly different between genotype subgroups (Kruskal–Wallis tests, P0.12). In a multivariate analysis, we found a significant, but limited effect (P=0.035, η2=0.031) of the CYP2C19*17 genotype on imipramine+desipramine concentrations. Although the CYP2C19*17 allele is associated with a significantly increased metabolism of imipramine, CYP2C19*17 genotyping will, in our view, not importantly contribute to dose management of patients on imipramine therapy guided by imipramine+desipramine plasma concentrations.

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References

  1. Slattery DA, Hudson AL, Nutt DJ . Invited review: the evolution of antidepressant mechanisms. Fundam Clin Pharmacol 2004; 18: 1–21.

    Article  CAS  PubMed  Google Scholar 

  2. Brøsen K . Some aspects of genetic polymorphism in the biotransformation of antidepressants. Therapie 2004; 59: 5–12.

    Article  PubMed  Google Scholar 

  3. Steimer W, Zöpf K, Von Amelunxen S, Pfeiffer H, Bachofer J, Popp J et al. Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers. Clin Chem 2004; 50: 1623–1633.

    Article  CAS  PubMed  Google Scholar 

  4. Gram LF . Metabolism of tricyclic antidepressants. A review. Dan Med Bull 1974; 21: 218–231.

    CAS  PubMed  Google Scholar 

  5. Madsen H, Rasmussen BB, Brøsen K . Imipramine demethylation in vivo: impact of CYP1A2, CYP2C19, and CYP3A4. Clin Pharmacol Ther 1997; 61: 319–324.

    Article  CAS  PubMed  Google Scholar 

  6. Linder MW, Prough RA, Valdes Jr R . Pharmacogenetics: a laboratory tool for optimizing therapeutic efficiency. Clin Chem 1997; 43: 254–266.

    CAS  PubMed  Google Scholar 

  7. Perry PJ, Pfohl BM, Holstad SG . The relationship between antidepressant response and tricyclic antidepressant plasma concentrations. A retrospective analysis of the literature using logistic regression analysis. Clin Pharmacokinet 1987; 13: 381–392.

    Article  CAS  PubMed  Google Scholar 

  8. Qin X-P, Xie H-G, Wang W, He N, Huang S-L, Xu Z-H et al. Effect of the gene dosage of CYP2C19 on diazepam metabolism in Chinese subjects. Clin Pharmacol Ther 1999; 66: 642–646.

    Article  CAS  PubMed  Google Scholar 

  9. Zanger UM, Raimundo S, Eichelbaum M . Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn-Schmiedebergs Arch Pharmacol 2004; 369: 23–37.

    Article  CAS  PubMed  Google Scholar 

  10. De Morais SMF, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA . The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994; 269: 15419–15422.

    CAS  PubMed  Google Scholar 

  11. Home page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee. http://www.imm.ki.se/CYPalleles/ (accessed December 2008).

  12. Tamminga WJ, Wemer J, Oosterhuis B, De Zeeuw RA, De Leij LFMH, Jonkman JHG . The prevalence of CYP2D6 and CYP2C19 genotypes in a population of healthy Dutch volunteers. Eur J Clin Pharmacol 2001; 57: 717–722.

    Article  CAS  PubMed  Google Scholar 

  13. 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: 594–598.

    CAS  PubMed  Google Scholar 

  14. Koyama E, Tanaka T, Chiba K, Kawakatsu S, Morinobu S, Totsuka S et al. Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4′-hydroxylation status in Japanese depressive patients. J Clin Psychopharmacol 1996; 16: 286–293.

    Article  CAS  PubMed  Google Scholar 

  15. Morinobu S, Tanaka T, Kawakatsu S, Totsuka S, Koyama E, Chiba K et al. Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy. Psychiatry Clin Neurosci 1997; 51: 253–257.

    Article  CAS  PubMed  Google Scholar 

  16. Amitai Y, Frischer H . Excess fatality from desipramine and dosage recommendations. Ther Drug Monit 2004; 26: 468–473.

    Article  CAS  PubMed  Google Scholar 

  17. Sim SC, Risinger C, Dahl M-L, 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: 103–113.

    Article  CAS  PubMed  Google Scholar 

  18. Kurzawski M, Gawrónska-Szklarz B, Wrzesniewska J, Siuda A, Starzynska T, Drozdzik M . Effect of CYP2C19*17 gene variant on Helicobacter pylori eradication in peptic ulcer patients. Eur J Clin Pharmacol 2006; 62: 877–880.

    Article  CAS  PubMed  Google Scholar 

  19. Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E . Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther 2008; 83: 322–327.

    Article  CAS  PubMed  Google Scholar 

  20. Ragia G, Arvanitidis KI, Tavridou A, Manolopoulos VG . Need for reassessment of reported CYP2C19 allele frequencies in various populations in view of CYP2C19*17 discovery: the case of Greece. Pharmacogenomics 2009; 10: 43–49.

    Article  CAS  PubMed  Google Scholar 

  21. Baldwin RM, Ohlsson S, Pedersen RS, Mwinyi J, Ingelman-Sundberg M, Eliasson E et al. Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. Br J Clin Pharmacol 2008; 65: 767–774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang G, Lei H-P, Li Z, Tan Z-R, Guo D, Fan L et al. The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers. Eur J Clin Pharmacol 2009; 65: 281–285.

    Article  CAS  PubMed  Google Scholar 

  23. Hunfeld NG, Mathot RA, Touw DJ, Van Schaik RH, Mulder PG, Franck PF et al. Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians. Br J Clin Pharmacol 2008; 65: 752–760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schenk PW, Van Fessem MAC, Verploegh-Van Rij S, Mathot RAA, Van Gelder T, Vulto AG et al. Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients. Mol Psychiatry 2008; 13: 597–605.

    Article  CAS  PubMed  Google Scholar 

  25. Informatorium Medicamentorum. Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie: The Hague, The Netherlands, 2006.

  26. Parfitt K (ed). Martindale: The Complete Drug Reference. Pharmaceutical Press: London, UK, 1999.

    Google Scholar 

  27. 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: 1181–1188.

    Article  CAS  PubMed  Google Scholar 

  28. Frère C, Cuisset T, Gaborit B, Alessi M-C, Hulot J-S . CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost 2009; 7: 1409–1411.

    Article  PubMed  Google Scholar 

  29. Ohlsson Rosenborg S, Mwinyi J, Andersson M, Baldwin RM, Pedersen RS, Sim SC et al. Kinetics of omeprazole and escitalopram in relation to the CYP2C19*17 allele in healthy subjects. Eur J Clin Pharmacol 2008; 64: 1175–1179.

    Article  CAS  PubMed  Google Scholar 

  30. Perry PJ, Zeilmann C, Arndt S . Tricyclic antidepressant concentrations in plasma: an estimate of their sensitivity and specificity as a predictor of response. J Clin Psychopharmacol 1994; 14: 230–240.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Part of this work was supported by an internal grant (Erasmus MC Revolving Fund, Top-Down, MEC 194.305/2000/168B).

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Correspondence to R H N van Schaik.

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Schenk, P., van Vliet, M., Mathot, R. et al. The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients. Pharmacogenomics J 10, 219–225 (2010). https://doi.org/10.1038/tpj.2009.50

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