Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects.
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.
Wuttke
Henrike
H
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Germany.
Rau
Thomas
T
Heide
Roland
R
Bergmann
Klaus
K
Böhm
Michael
M
Weil
Joachim
J
Werner
Dierk
D
Eschenhagen
Thomas
T
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
D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol