Impact of genotype on adverse effects during treatment with metoprolol: A prospective clinical study

Fux, Richard; Mörike, Klaus; Pröhmer, Anne M.T.; Delabar, Ursula; Schwab, Matthias; Schaeffeler, Elke; Lorenz, Gernot; Gleiter, Christoph H.; Eichelbaum, Michel; Kivistö, Kari T.

doi:10.1016/j.clpt.2005.07.004

Cited by 116 publications

(112 citation statements)

References 52 publications

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“…Only one other study was conducted in patients with HF as in this study. 19 Three of the studies were conducted primarily in individuals with hypertension, 15,20,21 one was in patients treated for acute myocardial infarct, 22 whereas one was a population-based study in which the indication was not mentioned. 23 Concentrations of the active S-enantiomer were measured in two of the studies 15,19 and intergenotype differences in S-metoprolol concentrations were observed, although these were not as marked in extent as in our study.…”

Section: Discussionmentioning

confidence: 99%

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

et al. 2009

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The aims of this study were to examine the relationships between CYP2D6 genotype and metoprolol dose, S-and R-metoprolol concentrations and clinical effects in patients with systolic heart failure. Data were obtained for 52 subjects, of which 27 had 2 functional alleles (24/27, CYP2D6*1/*1), 22 had 1 functional allele (18/22, CYP2D6*1/*4) and 3 had no functional alleles (CYP2D6*4/*4). Median dose-adjusted concentrations of S-metoprolol (active) were 6.3-and 3.2-fold higher in subjects with zero or one functional allele (P ¼ 0.016 and P ¼ 0.006), respectively, compared with subjects with two functional alleles. For the R-enantiomer (inactive), these concentrations were 10.7-and 3.7-fold higher (P ¼ 0.013 and P ¼ 0.003), respectively. Despite clear gene-concentration differences, no relationships between CYP2D6 genotype and dose or clinical effects could be shown. Although the number with no functional alleles was too small (n ¼ 3) to show effects, in patients with 1 functional allele other sources of variance are likely to be obscuring differences in clinical effects.

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Section: Discussionmentioning

confidence: 99%

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

et al. 2009

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“…CYP2D6 polymorphisms were identified for their dramatic effects on debrisoquine plasma levels, an antihypertensive no longer in use for these reasons (Eichelbaum and Gross 1990). Frequently used β-blockers including metoprolol, however, are also subject to CYP2D6 metabolism, which explains inter-individual differences in their efficacies and adverse effects (Fux et al 2005).…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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“…In this study, CYP2D6 genotype was not associated with tolerability to metoprolol CR/XL upon initiation of therapy. Together with the study results in other diseases [51,52], it appears that CYP2D6 genotype does not play a role in causing variability in responses (adverse or efficacious) to metoprolol. While other β-blockers have not been tested in this regard in HF, given that they are all less dependent on CYP2D6 for their metabolism than metoprolol, it seems unlikely that CYP2D6 variability would importantly affect their efficacy or tolerability.…”

Section: Genetic Associations With β-Blocker Tolerability In Hfmentioning

confidence: 86%

“…This may result in variable responses to the drug, particularly at therapy initiation, given the need to initiate β-blockers at low doses. Several studies also have determined whether the pharmacokinetic differences caused by the CYP2D6 polymorphisms are translated into variable adverse effects or efficacies in different diseases [46,[50][51][52]. In HF, only one study has tested this question [46].…”

Section: Genetic Associations With β-Blocker Tolerability In Hfmentioning

confidence: 99%

β-Blocker pharmacogenetics in heart failure

Shin

2008

Heart Fail Rev

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Abstractβ-Blockers (metoprolol, bisoprolol, and carvedilol) are a cornerstone of heart failure (HF) treatment. However, it is well recognized that responses to a β-blocker are variable among patients with HF. Numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to a β-blocker, including left ventricular ejection fraction improvement, survival, and hospitalization due to HF exacerbation. This review summarizes the pharmacogenetic data for β-blockers in patients with HF and discusses the potential implications of β-blocker pharmacogenetics for HF patients.

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Impact of genotype on adverse effects during treatment with metoprolol: A prospective clinical study

Abstract: CYP2D6 genotype-derived phenotype was not significantly associated with a propensity for adverse effects to develop during treatment with metoprolol. However, the results concerning tolerability of metoprolol in PMs were inconclusive because of the small number of PMs enrolled.

Cited by 116 publications

References 52 publications

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

Genetics of arterial hypertension and hypotension

β-Blocker pharmacogenetics in heart failure

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