An Investigation of CYP2D6 Genotype and Response to Metoprolol CR/XL During Dose Titration in Patients With Heart Failure: A MERIT-HF Substudy

被引：37

作者：

Batty, J. A. ^{[1
]}

Hall, A. S. ^{[2
]}

White, H. L. ^{[2
]}

Wikstrand, J. ^{[3
]}

de Boer, R. A. ^{[4
]}

van Veldhuisen, D. J. ^{[4
]}

van der Harst, P. ^{[4
]}

Waagstein, F. ^{[3
]}

Hjalmarson, A. ^{[3
]}

Kjekshus, J. ^{[5
]}

Balmforth, A. J. ^{[2
]}

机构：

[1] Univ Leeds, Sch Med, Leeds LS2 9JT, W Yorkshire, England

[2] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Div Epidemiol, Leeds, W Yorkshire, England

[3] Gothenburg Univ, Sahlgrenska Acad, Wallenberg Lab Cardiovasc Res, Gothenburg, Sweden

[4] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands

[5] Univ Oslo, Rikshosp, Dept Cardiol, N-0027 Oslo, Norway

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2014年 / 95卷 / 03期

关键词：

RANDOMIZED INTERVENTION TRIAL; CYTOCHROME-P450; 2D6; CLINICAL-OUTCOMES; TASK-FORCE; METABOLISM; OXIDATION; PHARMACOKINETICS; SUSCEPTIBILITY; COLLABORATION; POLYMORPHISMS;

D O I：

10.1038/clpt.2013.193

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：321 / 330

页数：10

共 44 条

[1] Titration of β-blockers in heart failure -: How to maximize benefit while minimizing adverse events [J].

Basile, JN .

POSTGRADUATE MEDICINE, 2003, 113 (03) :63-70

[2] Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis [J].

Beyeler, C ;

Armstrong, M ;

Bird, HA ;

Idle, JR ;

Daly, AK .

ANNALS OF THE RHEUMATIC DISEASES, 1996, 55 (01) :66-68

[3] Genetic Variation in the CYP2D6 Gene Is Associated With a Lower Heart Rate and Blood Pressure in β-Blocker Users [J].

Bijl, M. J. ;

Visser, L. E. ;

van Schaik, R. H. N. ;

Kors, J. A. ;

Witteman, J. C. M. ;

Hofman, A. ;

Vulto, A. G. ;

van Gelder, T. ;

Stricker, B. H. Ch .

CLINICAL PHARMACOLOGY & THERAPEUTICS, 2009, 85 (01) :45-50

[4] A Meta-Analysis of CYP2D6 Metabolizer Phenotype and Metoprolol Pharmacokinetics [J].

Blake, C. M. ;

Kharasch, E. D. ;

Schwab, M. ;

Nagele, P. .

CLINICAL PHARMACOLOGY & THERAPEUTICS, 2013, 94 (03) :394-399

[5] CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants [J].

Bradford, LD .

PHARMACOGENOMICS, 2002, 3 (02) :229-243

[6]

Brodde OE, 2003, ARZNEIMITTELFORSCH, V53, P814

[7] Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis [J].

Brown, MA ;

Edwards, S ;

Hoyle, E ;

Campbell, S ;

Laval, S ;

Daly, AK ;

Pile, KD ;

Calin, A ;

Ebringer, A ;

Weeks, DE ;

Wordsworth, BP .

HUMAN MOLECULAR GENETICS, 2000, 9 (11) :1563-1566

[8]

Chakeabarti S, 2010, J CARD FAIL, V16, pS53, DOI 10.1016/j.cardfail.2010.04.004

[9] ADVERSE-EFFECTS FROM METOPROLOL ARE NOT GENERALLY ASSOCIATED WITH OXIDATION STATUS [J].

CLARK, DWJ ;

MORGAN, AKW ;

WAALMANNING, H .

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1984, 18 (06) :965-967

[10] Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): an international survey [J].

Cleland, JGF ;

Cohen-Solal, A ;

Aguilar, JC ;

Dietz, R ;

Eastaugh, J ;

Follath, F ;

Freemantle, N ;

Gavazzi, A ;

van Gilst, WH ;

Hobbs, FDR ;

Korewicki, J ;

Madeira, HC ;

Preda, I ;

Swedberg, K ;

Widimsky, J .

LANCET, 2002, 360 (9346) :1631-1639

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