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CYP2D6 is a major determinant of metoprolol disposition and effects in hospitalized Russian patients treated for acute myocardial infarction

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

To investigate individual metabolism-related determinants of metoprolol disposition and effects in patients receiving the drug as standard treatment for acute myocardial infarction (AMI).

Methods

We recruited 187 AMI patients receiving metoprolol on clinical grounds and genotyped them for CYP2D6 *3, *4, *10, and gene duplication. Heart rates (HR) at admission and discharge were registered. Clinical details were derived from the case histories. Metoprolol and α-hydroxy-metoprolol were analyzed by HPLC in plasma before and after 2, 6 and 12 h post dose in the first 115 patients. HR at rest was registered after each sampling. Ventricular rhythm disturbance (VRD) association with CYP2D6 activity, found accidentally, was studied in a newly formed subgroup (n = 23).

Results

Metoprolol represented 85% of all beta-blocker prescriptions. CYP2D6 genotype distribution was comparable with other Caucasian populations. Genotypically poor metabolizers (PM, n = 2) exhibited the most pronounced bradycardia at discharge, while in the ultrarapid metabolizers (UM, n = 7) therapeutic effect was not achieved. Metoprolol and α-hydroxy-metoprolol plasma concentration AUCs differed significantly between the genotypes corresponding to predicted metabolic activity (P < 0.005). Correspondingly, the mean HRs were lower in PMs and increased with increasing number of active CYP2D6 genes (P < 0.05). Trough metoprolol concentrations were only quantifiable in patients with at least one mutated allele. Neither decreased cardiac ejection fraction nor age and gender influenced metoprolol disposition. Higher mean number of active CYP2D6 genes was found in patients with VRDs (2.2 vs. 1.7), which could not be clearly explained by metoprolol concentrations. CYP2D6 gene duplication was overrepresented in this group (22 vs. 2%, P = 0.0002).

Conclusion

Metoprolol disposition and effects are mainly controlled by CYP2D6 genotype. Patients with gene duplication are at high risk of not benefiting from treatment due to lower metoprolol concentrations. Higher CYP2D6 activity seems to be associated with VRDs complicating AMI, being a negative prognostic factor for patients’ survival.

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References

  1. WHOSTAT (2005)

  2. Antman EM, Anbe DT, Armstrong PW et al (2004) ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation 110(9):e82–e292

    PubMed  Google Scholar 

  3. Herlitz J, Karlson BW, Hjalmarson A (1993) Ten-year mortality rate after development of acute myocardial infarction in relation to clinical history and observations during hospital stay: experience from the Goteborg metoprolol trial. Coron Artery Dis 4(12):1077–1083

    Article  PubMed  CAS  Google Scholar 

  4. Lennard MS, Silas JH, Freestone S et al (1982) Oxidation phenotype–a major determinant of metoprolol metabolism and response. N Engl J Med 307(25):1558–1560

    PubMed  CAS  Google Scholar 

  5. Bertilsson L (2007) Metabolism of antidepressant and neuroleptic drugs by cytochrome p450s: clinical and interethnic aspects. Clin Pharmacol Ther 82(5):606–609

    Article  PubMed  CAS  Google Scholar 

  6. Goryachkina K, Burbello A, Boldueva S et al (2008) Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI). Eur J Clin Pharmacol 64(3):275–282

    Article  PubMed  CAS  Google Scholar 

  7. Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet Anal 14(5–6):143–149

    PubMed  CAS  Google Scholar 

  8. Garcia-Barcelo M, Chow LY, Chiu HF et al (2000) Genetic analysis of the CYP2D6 locus in a Hong Kong Chinese population. Clin Chem 46(1):18–23

    PubMed  CAS  Google Scholar 

  9. Lundqvist E, Johansson I, Ingelman-Sundberg M (1999) Genetic mechanisms for duplication and multiduplication of the human CYP2D6 gene and methods for detection of duplicated CYP2D6 genes. Gene 226(2):327–338

    Article  PubMed  CAS  Google Scholar 

  10. Bradford LD (2002) CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 3(2):229–243

    Article  PubMed  CAS  Google Scholar 

  11. Gaikovitch EA, Cascorbi I, Mrozikiewicz PM et al (2003) Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol 59(4):303–312

    Article  PubMed  CAS  Google Scholar 

  12. Opie L (2005) Drugs for the heart 6th edition

  13. Astra Zeneca FDA report NDA 19–962/S-027. 2005 [cited January, 2008]; Available from: http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/FDA_labels/019962.pdf.

  14. Elliot WJ (2001) Cyclic and circadian variations in cardiovascular events. Am J Hypertens 14(9 Pt 2):291S–295S

    Article  PubMed  CAS  Google Scholar 

  15. Rau T, Heide R, Bergmann K et al (2002) Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment. Pharmacogenetics 12(6):465–472

    Article  PubMed  CAS  Google Scholar 

  16. Ismail R, Teh LK (2006) The relevance of CYP2D6 genetic polymorphism on chronic metoprolol therapy in cardiovascular patients. J Clin Pharm Ther 31(1):99–109

    Article  PubMed  CAS  Google Scholar 

  17. Bertilsson L, Dahl ML, Dalen P et al (2002) Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 53(2):111–122

    Article  PubMed  CAS  Google Scholar 

  18. Koytchev R, Alken RG, Vlahov V et al (1998) Influence of the cytochrome P4502D6*4 allele on the pharmacokinetics of controlled-release metoprolol. Eur J Clin Pharmacol 54(6):469–474

    Article  PubMed  CAS  Google Scholar 

  19. Regardh CG, Johnsson G (1980) Clinical pharmacokinetics of metoprolol. Clin Pharmacokinet 5(6):557–569

    Article  PubMed  CAS  Google Scholar 

  20. Packer M, Lukas MA, Tenero DM et al (2006) Pharmacokinetic profile of controlled-release carvedilol in patients with left ventricular dysfunction associated with chronic heart failure or after myocardial infarction. Am J Cardiol 98(7A):39L–45L

    Article  PubMed  CAS  Google Scholar 

  21. Thurmann PA, Haack S, Werner U et al (2006) Tolerability of beta-blockers metabolized via cytochrome P450 2D6 is sex-dependent. Clin Pharmacol Ther 80(5):551–553

    Article  PubMed  CAS  Google Scholar 

  22. Luzier AB, Killian A, Wilton JH et al (1999) Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 66(6):594–601

    PubMed  CAS  Google Scholar 

  23. Rochon PA, Anderson GM, Tu JV et al (1999) Use of beta-blocker therapy in older patients after acute myocardial infarction in Ontario. CMAJ 161(11):1403–1408

    PubMed  CAS  Google Scholar 

  24. Olsson G, Wikstrand J, Warnold I et al (1992) Metoprolol-induced reduction in postinfarction mortality: pooled results from five double-blind randomized trials. Eur Heart J 13(1):28–32

    PubMed  CAS  Google Scholar 

  25. Park KC, Forman DE, Wei JY (1995) Utility of beta-blockade treatment for older postinfarction patients. J Am Geriatr Soc 43(7):751–755

    PubMed  CAS  Google Scholar 

  26. Herlitz J, Hjalmarson A, Holmberg S et al (1985) Tolerability to treatment with metoprolol in acute myocardial infarction in relation to age. Acta Med Scand 217(3):293–298

    PubMed  CAS  Google Scholar 

  27. Regardh CG, Landahl S, Larsson M et al (1983) Pharmacokinetics of metoprolol and its metabolite alpha-OH-metoprolol in healthy, non-smoking, elderly individuals. Eur J Clin Pharmacol 24(2):221–226

    Article  PubMed  CAS  Google Scholar 

  28. Dimenas ES, Dahlof CG, Heibel B et al (1990) Subjective symptoms and pharmacokinetics/dynamics of metoprolol CR in elderly subjects—a comparison with atenolol. Eur J Clin Pharmacol 38(6):571–578

    Article  PubMed  CAS  Google Scholar 

  29. Ellison KE, Gandhi G (2005) Optimising the use of beta-adrenoceptor antagonists in coronary artery disease. Drugs 65(6):787–797

    Article  PubMed  CAS  Google Scholar 

  30. Pratt CM, Yepsen SC, Bloom MG et al (1983) Evaluation of metoprolol in suppressing complex ventricular arrhythmias. Am J Cardiol 52(1):73–78

    Article  PubMed  CAS  Google Scholar 

  31. Zipes DP, Camm AJ, Borggrefe M et al (2006) ACC/AHA/ESC 2006 Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 114(10):e385–e484

    Article  PubMed  Google Scholar 

  32. Frossard M, Fuchs I, Leitner JM et al (2004) Platelet function predicts myocardial damage in patients with acute myocardial infarction. Circulation 110(11):1392–1397

    Article  PubMed  Google Scholar 

  33. Laghrissi-Thode F, Wagner WR, Pollock BG et al (1997) Elevated platelet factor 4 and beta-thromboglobulin plasma levels in depressed patients with ischemic heart disease. Biol Psychiatry 42(4):290–295

    Article  PubMed  CAS  Google Scholar 

  34. Elbekai RH, El-Kadi AO (2006) Cytochrome P450 enzymes: central players in cardiovascular health and disease. Pharmacol Ther 112(2):564–587

    Article  PubMed  CAS  Google Scholar 

  35. Yu AM, Idle JR, Herraiz T et al (2003) Screening for endogenous substrates reveals that CYP2D6 is a 5-methoxyindolethylamine O-demethylase. Pharmacogenetics 13(6):307–319

    Article  PubMed  CAS  Google Scholar 

  36. Bertilsson L, Alm C, De Las Carreras C et al (1989) Debrisoquine hydroxylation polymorphism and personality. Lancet 1(8637):555

    Article  PubMed  CAS  Google Scholar 

  37. Llerena A, Edman G, Cobaleda J et al (1993) Relationship between personality and debrisoquine hydroxylation capacity. Suggestion of an endogenous neuroactive substrate or product of the cytochrome P4502D6. Acta Psychiatr Scand 87(1):23–28

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Aleksandr V. Shabrov, the rector of St. Petersburg State Medical Academy named after I.I. Mechnikov, professor, and academician of Russian Academy of Medical Sciences; and Tommy Linne, coordinator of Karolinska Institute Research Training Program (KIRT) and associate professor. The help of biomedical analysts Lilleba Bohman in genotyping techniques and Jolanta Widen in HPLC techniques is gratefully acknowledged. The research was supported by the Swedish Institute (via KIRT), Heart-Lung Foundation and Swedish Research Council, Medicine (grant no. 3902). The study was approved by the local ethics committees of both universities.

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Authors and Affiliations

  1. Course of Clinical Pharmacology, Department of Hospital Therapy, St. Petersburg State Medical Academy named after I.I. Mechnikov, Piskarevsky Prospect, 47, 195 067, St. Petersburg, Russia

    Ksenia Goryachkina, Aleksandra Burbello & Svetlana Babak

  2. Department of Faculty Therapy, Clinic of Cardiology, St. Petersburg State Medical Academy named after I.I. Mechnikov, Piskarevsky Prospect, 47, 195 067, St. Petersburg, Russia

    Svetlana Boldueva

  3. Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Huddinge, SE-141 86, Stockholm, Sweden

    Ksenia Goryachkina, Ulf Bergman & Leif Bertilsson

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  1. Ksenia Goryachkina
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  2. Aleksandra Burbello
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  3. Svetlana Boldueva
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  4. Svetlana Babak
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  5. Ulf Bergman
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  6. Leif Bertilsson
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Correspondence to Ksenia Goryachkina.

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Goryachkina, K., Burbello, A., Boldueva, S. et al. CYP2D6 is a major determinant of metoprolol disposition and effects in hospitalized Russian patients treated for acute myocardial infarction. Eur J Clin Pharmacol 64, 1163–1173 (2008). https://doi.org/10.1007/s00228-008-0525-3

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