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

Sharp, Caroline F.; Gardiner, Sharon J.; Jensen, Berit Packert; Roberts, Rebecca; Troughton, Richard W.; Lainchbury, JG; Begg, Evan J.

doi:10.1038/tpj.2009.9

Cited by 23 publications

(28 citation statements)

References 36 publications

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“…The results of the presented study indicated higher concentrations of metoprolol among the CYP2D6*1/*3 heterozygotes with one nonfunctional allele (EMs). Similar findings were reported by Sharp et al In their research the median concentrations were 3.2-fold higher in subjects with one functional allele compared with subjects with two functional alleles [15].…”

Section: Resultssupporting

confidence: 90%

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

Wojtczak

Skrętkowicz

2014

Pharmacological Reports

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The currently used b-blockers differ in their selectivity for b 1 -and b 2 -adrenergic receptors, lipophilicity and route of elimination. Metoprolol is one of the most commonly used b-blockers in the treatment of ischemic heart disease. Metoprolol is a lipophilic b 1 -selective blocker. This drug is well absorbed from the gastrointestinal tract and undergoes extensive distribution in body tissues; it also passes through the blood-brain barrier. The highest plasma concentration value of metoprolol is reached approximately 2 h after administration of a single dose. Metoprolol is extensively metabolized (oxidation) in the liver by the CYP2D6 isoenzyme of cytochrome P450 [2].The gene encoding the CYP2D6 enzyme is highly polymorphic. The CYP2D6 oxidation polymorphism has a major impact on the Background:Metoprolol is the one of the most commonly used b-blockers in the treatment of ischemic heart disease and it is extensively metabolized in the liver undergoing oxidation by CYP2D6 isoenzyme of cytochrome P450. Gene encoding the CYP2D6 enzyme is characterized by genetic polymorphism. The CYP2D6 oxidation polymorphism has a major impact on the effectiveness and safety of the treatment. The aim of the study was to evaluate the relationship between plasma concentration of metoprolol and the CYP2D6 genotype in patients with ischemic heart disease. Methods: Fifty patients were interviewed and subsequently enrolled into the study. The patients received metoprolol twice daily at a dose of 50 mg. The blood samples were analyzed for two major defective alleles for CYP2D6 -CYP2D6*4 and CYP2D6*3 -by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Metoprolol concentration in plasma was determined by using the new and unique high-performance liquid chromatography (HPLC) method in the author's own modification with Corona CAD detector (Charged Aerosol Detection). Results: In the test group, genotypes conditioning poor oxidation (PM) occurred in 3 patients (6%), while 47 patients (94%) had genotypes coding for extensive metabolism (EM). Patients with PM genotypes had significantly higher plasma concentrations of metoprolol than the patients with EM genotype (mean 92.25 AE SD 36.78 ng/ml vs. mean 168.22 AE SD 5.61 ng/ml, respectively). Established relationships were statistically significant (NIR test, p = 0.0009). Conclusions: This study demonstrated that the CYP2D6 genotype remains a major determinant of the metoprolol plasma concentrations. The pharmacogenetic effect is likely to have consequences on both, the clinical benefit of metoprolol treatment and adverse drug reactions. The use of Corona CAD detector seems to be a very good alternative method for the determination of metoprolol concentration in plasma.

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Section: Resultssupporting

confidence: 90%

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

Wojtczak

Skrętkowicz

2014

Pharmacological Reports

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“…As a result, it is widely employed clinically (see examples [18][19][20]). An example of a typical steady-state PKPD model is given by: …”

Section: Steady-state Pkpdmentioning

confidence: 99%

Understanding the time course of pharmacological effect: a PKPD approach

Wright

Winter

Duffull

2011

Brit J Clinical Pharma

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The key concepts that underpin the choice of drug and dosing regimen are an understanding of the drugs' effectiveness, the potential for adverse effects, and the expected time course over which both desired and adverse effects are likely to occur. Research in clinical pharmacology should therefore address three fundamental questions: (1) What is the magnitude of drug effects (beneficial or adverse) from a given dose? (2) How quickly will any given effects occur? (3) How long will these effects last? Under steady-state conditions, only the magnitude of drug effects can be examined. This requires researchers to consider non-steady-state conditions, which require more complex models and an understanding of the mechanisms that drive the time course of drug effect. The aim of this review is to provide a conceptual framework for understanding the time course of drug effects using pharmacokinetic-pharmacodynamic models. Key examples will illustrate how this can inform the optimal use of drugs in the clinic.

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“…Altered drug clearance as a result of CYP2D6 polymorphisms has striking consequences on metoprolol pharmacokinetics (99), with the elimination half-life ranging from 2.8 h in extensive metabolizers to 7.5 h in poor metabolizers (172). Indeed, multiple studies in normal subjects, hypertensive patients, and individuals with heart failure have found a strong relationship between CYP2D6 genotype, metabolizer phenotype, and metoprolol concentrations, even after chronic treatment at standard doses (252,277). Accordingly, the possible consequences of altered metabolic clearance include altered drug efficacy (because of insufficient drug levels in extensive metabolizers or increased drug levels in poor metabolizers) or increased toxicity (because of high drug levels in poor metabolizers).…”

Section: Cypd2d6 Polymorphismsmentioning

confidence: 99%

“…Poor metabolizers represent only a small fraction of the general population (7-10% of the Caucasian population), so it is understandable that these findings have not been reproduced in smaller studies that were insufficiently powered to independently examine this subgroup. When these types of analyses have compared metoprolol effect in subjects with two functional CYP2D6 alleles (i.e., extensive metabolizers, 70% of population) versus combined intermediate and poor metabolizers (15 and 10% of the population, respectively), differences have not been significant (277). Thus, while there is little doubt that CYP2D6 genotype can determine metabolizer status and affect metoprolol levels, increased drug effect is clearly significant only in poor metabolizers who represent a small fraction of the population.…”

Section: Cypd2d6 Polymorphismsmentioning

confidence: 99%

Adrenergic Signaling Polymorphisms and Their Impact on Cardiovascular Disease

Dorn

2010

Physiological Reviews

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This review examines the impact of recent discoveries defining personal genetics of adrenergic signaling polymorphisms on scientific discovery and medical practice related to cardiovascular diseases. The adrenergic system is the major regulator of minute-by-minute cardiovascular function. Inhibition of adrenergic signaling with pharmacological beta-adrenergic receptor antagonists (beta-blockers) is first-line therapy for heart failure and hypertension. Advances in pharmacology, molecular biology, and genetics of adrenergic signaling pathways have brought us to the point where personal genetic differences in adrenergic signaling factors are being assessed as determinants of risk or progression of cardiovascular disease. For a few polymorphisms, functional data generated in cell-based systems, genetic mouse models, and pharmacological provocation of human subjects are concordant with population studies that suggest altered risk of cardiovascular disease or therapeutic response to beta-blockers. For the majority of adrenergic pathway polymorphisms however, published data conflict, and the clinical relevance of individual genotyping remains uncertain. Here, the current state of laboratory and clinical evidence that adrenergic pathway polymorphisms can affect cardiovascular pathophysiology is comprehensively reviewed and compared, with a goal of placing these data in the broad context of potential clinical applicability.

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

Cited by 23 publications

References 36 publications

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

Understanding the time course of pharmacological effect: a PKPD approach

Adrenergic Signaling Polymorphisms and Their Impact on Cardiovascular Disease

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