title: An investigation of CYP2D6 genotype and response to metoprolol CR/XL during dose titration in patients with heart failure: a MERIT-HF substudy.
abstract: To explore the pharmacogenetic effects of the cytochrome P450 (CYP)2D6 genotype in patients with systolic heart failure treated using controlled/extended-release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional *4 allele (1846G>A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6*4 allele (EM: *1*1, 60.4%; IM: *1*4, 35.8%; and PM: *4*4, 3.8%). Plasma metoprolol concentrations were 2.1-/4.6-fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6*4 allele dose-response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT-HF-defined titration schedule remains recommended for all patients, regardless of genotype.
authors.affiliation: School of Medicine, University of Leeds, Leeds, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Batty
authors.affiliation: Division of Epidemiology, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Hall
authors.affiliation: Division of Epidemiology, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
authors.forename: H L
authors.initials: HL
authors.lastname: White
authors.affiliation: Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Wikstrand
authors.affiliation: Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: R A
authors.initials: RA
authors.lastname: de Boer
authors.affiliation: Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.affiliation: Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Waagstein
authors.affiliation: Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: Å
authors.initials: Å
authors.lastname: Hjalmarson
authors.affiliation: Department of Cardiology, Rikshospitalet, University of Oslo, Oslo, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Kjekshus
authors.affiliation: Division of Epidemiology, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Balmforth
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D012307:Risk Factors; D013237:Stereoisomerism; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D004247:DNA; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol