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Clin Pharmacol Ther. 2014 Mar;95(3):321-30. doi: 10.1038/clpt.2013.193. Epub 2013 Sep 30.

An investigation of CYP2D6 genotype and response to metoprolol CR/XL during dose titration in patients with heart failure: a MERIT-HF substudy.

Author information

1
School of Medicine, University of Leeds, Leeds, UK.
2
Division of Epidemiology, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
3
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
4
Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
5
Department of Cardiology, Rikshospitalet, University of Oslo, Oslo, Norway.

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.

PMID:
24193112
DOI:
10.1038/clpt.2013.193
[Indexed for MEDLINE]

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