European Journal of Clinical Pharmacology

, Volume 64, Issue 3, pp 275–282 | Cite as

Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI)

  • Ksenia Goryachkina
  • Aleksandra Burbello
  • Svetlana Boldueva
  • Svetlana Babak
  • Ulf Bergman
  • Leif Bertilsson
Pharmacokinetics and Disposition



To investigate the influence of paroxetine on metoprolol concentrations and its effect in patients treated for acute myocardial infarction (AMI) who are routinely given paroxetine as a co-treatment of depression.


We recruited 17 depressed AMI patients who received metoprolol as a routine part of their therapy (mean dose 75 ± 39 mg/day). Patients were genotyped for CYP2D6 *3, *4 and gene duplication. Metoprolol and α-hydroxy-metoprolol were analyzed in plasma 0, 2, 6 and 12 h post-dose. Heart rates (HR) at rest were registered after each sampling. Paroxetine 20 mg daily was then administered, and all measurements were repeated on day 8.


All patients were genotypically extensive metabolizers (EMs) (nine with *1/*1 and eight with *1/*3 or *4). Following the administration of paroxetine, mean metoprolol areas under the concentration–time curve (AUC) increased (1064 ± 1213 to 4476 ± 2821 nM × h/mg per kg, P = 0.0001), while metabolite AUCs decreased (1492 ± 872 to 348 ± 279 n M × h/mg per kg, P < 0.0001), with an increase of metabolic ratios (MR) (0.9 ± 1.3 to 26 ± 29; P < 0.0001). Mean HRs were significantly lower after the study week at each time point. Mean area under the HR versus time curve (AUEC) decreased (835 ± 88 to 728 ± 84 beats × h/min; P = 0.0007). Metoprolol AUCs correlated with patients’ AUECs at the baseline (Spearman r  = −0.64, P < 0.01), but not on the eighth day of the study. A reduction of metoprolol dose was required in two patients due to excessive bradycardia and severe orthostatic hypotension. No other adverse effects of the drugs were identified.


A pronounced inhibition of metoprolol metabolism by paroxetine was observed in AMI patients, but without serious adverse effects. We suggest, however, that the metoprolol dose is controlled upon initiation and withdrawal of paroxetine.


CYP2D6 Drug interaction Metoprolol Myocardial infarction Paroxetine 



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


  1. 1.
    Sorensen C, Friis-Hasche E, Haghfelt T, Bech P (2005) Postmyocardial infarction mortality in relation to depression: a systematic critical review. Psychother Psychosom 74(2):69–80CrossRefGoogle Scholar
  2. 2.
    Thombs BD, Bass EB, Ford DE et al (2006) Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med 21(1):30–38PubMedCrossRefGoogle Scholar
  3. 3.
    Chazov EI, Oganov RG, Pogosova GV et al (2007) Clinico-epidemiological program of the study of depression in cardiological practice in patients with arterial hypertension and ischemic heart disease (COORDINATA). Kardiologiia 47(3):29–37PubMedGoogle Scholar
  4. 4.
    Jiang W, Davidson JR (2005) Antidepressant therapy in patients with ischemic heart disease. Am Heart J 150(5):871–881PubMedCrossRefGoogle Scholar
  5. 5.
    Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340(2–3):249–258PubMedCrossRefGoogle Scholar
  6. 6.
    Sauer WH, Berlin JA, Kimmel SE (2003) Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 108(1):32–36PubMedCrossRefGoogle Scholar
  7. 7.
    Roose SP, Laghrissi-Thode F, Kennedy JS et al (1998) Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 279(4):287–291PubMedCrossRefGoogle Scholar
  8. 8.
    Pollock BG, Laghrissi-Thode F, Wagner WR (2000) Evaluation of platelet activation in depressed patients with ischemic heart disease after paroxetine or nortriptyline treatment. J Clin Psychopharmacol 20(2):137–140PubMedCrossRefGoogle Scholar
  9. 9.
    Yeragani VK, Pohl R, Balon R, Ramesh C, Glitz D et al (2002) Major depression with ischemic heart disease: effects of paroxetine and nortriptyline on long-term heart rate variability measures. Biol Psychiatry 52(5):418–429PubMedCrossRefGoogle Scholar
  10. 10.
    Glassman AH, O’Connor CM, Califf RM et al (2002) Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 288(6):701–709PubMedCrossRefGoogle Scholar
  11. 11.
    Molden E, Garcia BH, Braathen P, Eggen AE (2005) Co-prescription of cytochrome P450 2D6/3A4 inhibitor-substrate pairs in clinical practice. A retrospective analysis of data from Norwegian primary pharmacies. Eur J Clin Pharmacol 61(2):119–125PubMedCrossRefGoogle Scholar
  12. 12.
    Hemeryck A, Belpaire FM (2002) Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab 3(1):13–37PubMedCrossRefGoogle Scholar
  13. 13.
    Hjalmarson A, Herlitz J, Holmborg S et al (1983) The Goteborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction. Circulation 67(6 Pt 2):I26–I32PubMedGoogle Scholar
  14. 14.
    Chen ZM, Pan HC, Chen YP et al (2005) Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366(9497):1622–1632PubMedCrossRefGoogle Scholar
  15. 15.
    Freemantle N, Cleland J, Young P et al (1999) Beta blockade after myocardial infarction: systematic review and meta regression analysis. Br Med J 318(7200):1730–1737Google Scholar
  16. 16.
    Olsson G, Rehnqvist N, Sjo’gren A, Erhardt L, Lundman T (1985) Long-term treatment with metoprolol after myocardial infarction: effect on 3 year mortality and morbidity. J Am Coll Cardiol 5(6):1428–1437PubMedCrossRefGoogle Scholar
  17. 17.
    Everts B, Karlson B, Abdon N-J, Herlitz J, Hedner T et al (1997) Effects and pharmacokinetics of high dose metoprolol on chest pain in patients with suspected or definite acute myocardial infarction. Eur J Clin Pharmacol 53(1):23–31PubMedCrossRefGoogle Scholar
  18. 18.
    McGourty JC, Silas JH, Lennard MS, Tucker GT, Woods HF et al (1985) Metoprolol metabolism and debrisoquine oxidation polymorphism-population and family studies. Br J Clin Pharmacol 20(6):555–566PubMedGoogle Scholar
  19. 19.
    Ingelman-Sundberg M (2005) Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 5(1):6–13PubMedCrossRefGoogle Scholar
  20. 20.
    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):303–312PubMedCrossRefGoogle Scholar
  21. 21.
    Rau T, Wohlleben G, Wuttke H, Thuerauf N, Lunkenheimer J et al (2002) Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment. Pharmacogenetics 12(6):465–472PubMedCrossRefGoogle Scholar
  22. 22.
    Ramenskaya GV et al (2002) Pheno- and genotyping the prescription of drugs metabolized by CYP2D6. Bull Exp Biol Med 134(2):159–160PubMedCrossRefGoogle Scholar
  23. 23.
    Wuttke H, Rau T, Heide R, Bergmann K, Böhm M et al (2002) Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects. Clin Pharmacol Ther 72(4):429–437PubMedCrossRefGoogle Scholar
  24. 24.
    Fux R, Morike K, Prohmer AM et al (2005) Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study. Clin Pharmacol Ther 78(4):378–387PubMedCrossRefGoogle Scholar
  25. 25.
    Zineh I, Beitelshees AL, Gaedigk A, Walker JR et al (2004) Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension. Clin Pharmacol Ther 76(6):536–544PubMedCrossRefGoogle Scholar
  26. 26.
    Hemeryck A, Lefebvre RA, De Vriendt C, Belpaire FM (2000) Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 67(3):283–291PubMedCrossRefGoogle Scholar
  27. 27.
    Kendall MJ, John VA, Quarterman CR, Welling PG (1980) A single and multiple dose pharmacokinetic and pharmacodynamic comparison of conventional and slow-release metroprolol. Eur J Clin Pharmacol 17(2):87–92PubMedCrossRefGoogle Scholar
  28. 28.
    Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67(6):361–370PubMedCrossRefGoogle Scholar
  29. 29.
    Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62PubMedGoogle Scholar
  30. 30.
    Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 14(5–6):143–149PubMedGoogle Scholar
  31. 31.
    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):327–338PubMedCrossRefGoogle Scholar
  32. 32.
    Regardh CG, Johnsson G (1980) Clinical pharmacokinetics of metoprolol. Clin Pharmacokinet 5(6):557–569PubMedCrossRefGoogle Scholar
  33. 33.
    Koytchev R, Alken RG, Vlahov V, Kirkov V, Kaneva R et al (1998) Influence of the cytochrome P4502D6*4 allele on the pharmacokinetics of controlled-release metoprolol. Eur J Clin Pharmacol 54(6):469–474PubMedCrossRefGoogle Scholar
  34. 34.
    Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK et al (2006) AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 113(19):2363–2372PubMedCrossRefGoogle Scholar
  35. 35.
    Toon S, Davidson EM, Garstang FM, Batra H, Bowes RJ, Rowland M (1988) The racemic metoprolol H2-antagonist interaction. Clin Pharmacol Ther 43(3):283–289PubMedCrossRefGoogle Scholar
  36. 36.
    The MIAMI Trial Research Group (1985) Metoprolo in acute mycardial infarction. Other clinical findings and tolerability. Am J Cardiol 56(14):39G–46GGoogle Scholar
  37. 37.
    Herlitz J et al (2000) Long-term mortality after acute myocardial infarction in relation to prescribed dosages of a beta-blocker at hospital discharge. Cardiovasc Drugs Ther 14(6):589-595.Google Scholar
  38. 38.
    Mautz DS, Nelson WL, Shen DD (1995) Regioselective and stereoselective oxidation of metoprolol and bufuralol catalyzed by microsomes containing cDNA-expressed human P4502D6. Drug Metab Dispos 23(4):513–517PubMedGoogle Scholar
  39. 39.
    Brynne N, Bottiger Y, Hallen B, Bertilsson L (1999) Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole. Br J Clin Pharmacol 47(2):145–150PubMedCrossRefGoogle Scholar
  40. 40.
    Özdemir V, Naranjo CA, Shulman RW, Herrmann N et al (1998) Determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition by paroxetine and fluvoxamine in vivo. J Clin Psychopharmacol 18(3):198–207PubMedCrossRefGoogle Scholar
  41. 41.
    Thurmann PA, Haack S, Werner U, Szymanski J et al (2006) Tolerability of beta-blockers metabolized via cytochrome P450 2D6 is sex-dependent. Clin Pharmacol Ther 80(5):551–553PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Ksenia Goryachkina
    • 1
    • 3
  • Aleksandra Burbello
    • 1
  • Svetlana Boldueva
    • 2
  • Svetlana Babak
    • 1
  • Ulf Bergman
    • 3
  • Leif Bertilsson
    • 3
  1. 1.Course of Clinical Pharmacology, Department of Hospital TherapySt. Petersburg I.I. Mechnikov State Medical AcademySt PetersburgRussia
  2. 2.Department of Faculty Therapy, Clinic of CardiologySt. Petersburg I.I. Mechnikov State Medical AcademySt PetersburgRussia
  3. 3.Department of Laboratory Medicine, Division Clinical Pharmacology, Karolinska InstitutetKarolinska University HospitalHuddinge–StockholmSweden

Personalised recommendations