title: Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study.
abstract: OBJECTIVE
  Our objective was to study the impact of the cytochrome P450 (CYP) 2D6 polymorphism on the tolerability of metoprolol in a real-life primary care setting. The adverse effects studied comprised effects related to the central nervous system, cardiovascular effects, and sexual dysfunction.
  
  
  METHODS
  Patients in whom treatment with metoprolol was considered were enrolled into this prospective, 6-week multicenter study. The dosage of metoprolol was determined on an individual basis and could be freely adjusted on clinical grounds. The indication for treatment was hypertension in about 90% of cases. Systolic and diastolic blood pressure, resting heart rate, and plasma metoprolol and alpha-hydroxymetoprolol concentrations were measured. CYP2D6 genotyping covered alleles *3 to *10 and *41 and the duplications. Possible adverse effects of metoprolol were systematically assessed over a 6-week period by means of standardized rating scales and questionnaires.
  
  
  RESULTS
  The final study population comprised 121 evaluable patients (all white patients); among them, there were 5 ultrarapid metabolizers (UMs) (4.1%), 91 extensive metabolizers (EMs) (75%), 21 intermediate metabolizers (IMs) (17%), and 4 poor metabolizers (PMs) (3.3%). Plasma metoprolol concentrations normalized for the daily dose and metoprolol/alpha-hydroxymetoprolol ratios at steady state were markedly influenced by CYP2D6 genotype and displayed a gene-dose effect. The median of the dose-normalized metoprolol concentration was 0.0088 ng/mL, 0.047 ng/mL, 0.34 ng/mL, and 1.34 ng/mL among UMs, EMs, IMs, and PMs, respectively (P<.0001). There was no significant association between CYP2D6 genotype-derived phenotype (EMs and UMs combined versus PMs and IMs combined) and adverse effects during treatment with metoprolol. There was a tendency toward a more frequent occurrence of cold extremities in the PM plus IM group as compared with the EM plus UM group (16.0% versus 4.2%, P=.056; relative risk, 3.8 [95% confidence interval, 1.03--14.3]).
  
  
  CONCLUSIONS
  CYP2D6 genotype-derived phenotype was not significantly associated with a propensity for adverse effects to develop during treatment with metoprolol. However, the results concerning tolerability of metoprolol in PMs were inconclusive because of the small number of PMs enrolled.
authors.affiliation: Abteilung Klinische Pharmakologie, Lehrbereich Allgemeinmedizin der Medizinischen Fakultät, and Koordinierungszentrum Klinische Studien, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Fux
authors.forename: Klaus
authors.initials: K
authors.lastname: Mörike
authors.forename: Anne M T
authors.initials: AM
authors.lastname: Pröhmer
authors.forename: Ursula
authors.initials: U
authors.lastname: Delabar
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.forename: Gernot
authors.initials: G
authors.lastname: Lorenz
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Gleiter
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Kari T
authors.initials: KT
authors.lastname: Kivistö
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008790:Metoprolol / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; C029504:alpha-hydroxymetoprolol; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol