title: Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment.
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.
authors.affiliation: Institute of Clinical and Experimental Pharmacology and Toxicology, Friedrich-Alexander University Erlangen-Nuremberg, Fahrstr. 17, 91054 Erlangen, Germany. Rau@pharmakologie.uni-erlangen.de
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: Henrike
authors.initials: H
authors.lastname: Wuttke
authors.forename: Ulrike
authors.initials: U
authors.lastname: Werner
authors.forename: Nico
authors.initials: N
authors.lastname: Feifel
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000201:enzymology*; D003430:Cross-Sectional Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004334:Drug Administration Schedule; D005260:Female; D005787:Gene Frequency / Q000187:drug effects; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D008790:Metoprolol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D044465:White People / Q000235:genetics
chemical_list: D000319:Adrenergic beta-Antagonists; D017931:DNA Primers; C029504:alpha-hydroxymetoprolol; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol