Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment.
Pharmacogenetics
; 12(6): 465-72, 2002 Aug.
Article
in En
| MEDLINE
| ID: mdl-12172215
ABSTRACT
The beta1 selective beta-blocker metoprolol is metabolized predominantly but not exclusively by CYP2D6. Due to the polymorphism of the CYP2D6 gene, CYP2D6 activity varies markedly between individuals. Consequently, after short-term administration metoprolol plasma concentrations were found to be several fold higher in poor metabolizers than in extensive metabolizers. However, it is currently not known, whether the impact of the CYP2D6 polymorphism persists during long-term therapy, since alternate mechanisms of elimination or metabolism could be effective in this setting. The study comprised 91 Caucasian patients on long-term treatment with metoprolol (median duration of treatment 12.6 months; median daily drug dose 47.5 mg/day). Metoprolol and alpha-OH-metoprolol plasma concentrations were assessed by HPLC. Genotyping detected the null alleles (*0) *3, *4, *5, *6, *7, *8, *12, *14, *15, the alleles *9, *10 and *41 associated with reduced enzymatic activity as well as the fully functional alleles *1 and *2. Genotype and allele frequencies were in accordance with published frequencies for the German population. The plasma metabolic ratio of metoprolol/alpha-OH-metoprolol was markedly affected by the genotype (P < 0.0001). In accordance, median adjusted metoprolol plasma concentrations were 6.2- and 3.9-fold higher in patients with *0/*0 genotypes (n = 8) and intermediate genotypes (n = 10), respectively, as compared to those with two fully functional alleles (n = 31; P < 0.01). In summary, the pronounced effect of the CYP2D6 genotype persists during long-term therapy, affecting both metabolic ratio and metoprolol plasma concentration.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Coronary Artery Disease
/
Adrenergic beta-Antagonists
/
Cytochrome P-450 CYP2D6
/
Gene Frequency
/
Hypertension
/
Metoprolol
Type of study:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prevalence_studies
/
Risk_factors_studies
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
Pharmacogenetics
Year:
2002
Document type:
Article
Affiliation country:
Germany