title: Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects.
abstract: OBJECTIVE
  The CYP2D6 genotype is a major determinant of interindividual differences in metoprolol plasma clearance. Cytochrome P450 2D6 (CYP2D6) poor metabolizers exhibit 3- to 10-fold higher plasma concentrations after administration of metoprolol than extensive metabolizers. However, the impact of the CYP2D6 genotype on the occurrence of adverse effects of metoprolol remains controversial. This study addressed whether the incidence of poor metabolizers was higher in patients with metoprolol-associated adverse effects than in the German population at large.
  
  
  METHODS
  Approximately 1200 German physicians were asked to report on patients who had experienced pronounced adverse effects in association with administration of metoprolol. CYP2D6 genotypes were determined with a combination of allele-specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. The adverse effects, consisting of symptoms related to beta-adrenergic receptor blockade and nonspecific symptoms, were recorded by use of a standardized questionnaire.
  
  
  RESULTS
  Twenty-four patients were included in the study. Nine patients had 2 null alleles (poor metabolizer genotype; 38%); the remaining 15 had either 1 null allele (n = 7) or no null alleles (n = 8). Therefore the occurrences of poor metabolizer genotypes in the study population were 4.9- and 5.2-fold more frequent, respectively, than that found in unselected members of the German population in two large studies (P <.0001; chi(2) test).
  
  
  CONCLUSIONS
  These data showed that CYP2D6 poor metabolizers had a 5-fold higher risk for development of adverse effects during metoprolol treatment than patients who were not poor metabolizers. Because the absolute risk of adverse effects of metoprolol is unknown, the clinical relevance of the CYP2D6 genotype for metoprolol therapy has to be determined in a prospective manner.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Wuttke
authors.forename: Thomas
authors.initials: T
authors.lastname: Rau
authors.forename: Roland
authors.initials: R
authors.lastname: Heide
authors.forename: Klaus
authors.initials: K
authors.lastname: Bergmann
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Joachim
authors.initials: J
authors.lastname: Weil
authors.forename: Dierk
authors.initials: D
authors.lastname: Werner
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
mesh_terms: D000328:Adult; D000368:Aged; D016009:Chi-Square Distribution; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency / Q000187:drug effects; D005838:Genotype; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000009:adverse effects* / Q000097:blood; D008875:Middle Aged; D012189:Retrospective Studies; D018709:Statistics, Nonparametric
chemical_list: D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol