title: CYP2D6 is a major determinant of metoprolol disposition and effects in hospitalized Russian patients treated for acute myocardial infarction.
abstract: OBJECTIVE
  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 alpha-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 alpha-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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Course of Clinical Pharmacology, Department of Hospital Therapy, St. Petersburg State Medical Academy named after I.I. Mechnikov, Piskarevsky Prospect 47, 195067 St. Petersburg, Russia. ksenia_goryachkina@yahoo.com
authors.forename: Ksenia
authors.initials: K
authors.lastname: Goryachkina
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Burbello
authors.forename: Svetlana
authors.initials: S
authors.lastname: Boldueva
authors.forename: Svetlana
authors.initials: S
authors.lastname: Babak
authors.forename: Ulf
authors.initials: U
authors.lastname: Bergman
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D006760:Hospitalization; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D008790:Metoprolol / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D011446:Prospective Studies; D012189:Retrospective Studies; D012426:Russia; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol