Introduction

Metoprolol is a beta-blocker indicated for the treatment of various cardiovascular diseases, including hypertension, arrhythmias, angina, myocardial infarction, and heart failure (HF). Metoprolol selectively blocks beta₁-adrenoreceptors, which are expressed predominantly in cardiac tissue. The primary therapeutic effect resulting from the blockade of these receptors is a reduction in heart rate and a decrease in the force of heart contractions.

Metoprolol is metabolized extensively by the hepatic CYP2D6 enzyme. Approximately 8% of Caucasians and 2% of most other populations have absent CYP2D6 activity and are known as “CYP2D6 poor metabolizers (PM).” In addition, several drugs inhibit CYP2D6 activity, such as bupropion, quinidine, fluoxetine, paroxetine, and propafenone.

The FDA-approved drug label for metoprolol states that CYP2D6 PM and normal metabolizers (NM) who concomitantly take drugs that inhibit CYP2D6 will have increased metoprolol blood levels, decreasing metoprolol’s cardioselectivity; co-medication with CYP2D6 inhibitors warrants close monitoring (1). (Table 1) Beta-blockers, such as metoprolol, have been demonstrated in several large clinical trials to be safe and effective for the treatment of individuals with cardiovascular disease. As a mainstay of therapy associated with improvements in quality of life, hospitalization rates, and survival (2, 3), clinical care pathways that might lead to the underutilization of beta-blockers require scrutiny. It is common clinical practice to adjust the dose of metoprolol according to individual heart rate until either the target or maximum tolerated dose is reached. The FDA does not specifically comment on the role of genetic testing for initiating therapy.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that CYP2D6 PM should initiate metoprolol therapy at the lowest recommended starting dose, and titration should be performed with care and close monitoring for bradycardia. (Table 2) Standard dosing and care are recommended for intermediate metabolizers (IM) and NM of CYP2D6, but no recommendation is made for ultrarapid metabolizers (UM) given the limited data on this phenotype and beta-blocker response. (4)

The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Pharmacists Association (KNMP) has also published metoprolol dosing recommendations based on CYP2D6 genotype. For individuals who have a CYP2D6 gene variation that reduces the conversion of metoprolol to inactive metabolites (namely, the IM and PM phenotype), DPWG states that the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia. For CYP2D6 PM or IM, if a gradual reduction in heart rate is desired, or in the event of symptomatic bradycardia, DPWG recommends increasing the dose of metoprolol in smaller steps, prescribing no more than 25% (PM) or 50% (IM) of the standard dose, or both. For CYP2D6 UM, DPWG indicates that clinical response is hardly decreased at a dose of 200 mg/day. However, if efficacy is insufficient at this maximum dose, the DPWG recommends increasing the dose based on effectiveness and side effects up to a maximum of 2.5 times the normal dose, or selecting an alternative. (Table 3) (5).

Drug: Metoprolol

Metoprolol is a commonly prescribed drug that belongs to the drug class of beta-adrenoreceptor antagonists, also known as “beta-blockers”. Metoprolol is indicated to treat hypertension, angina, myocardial infarction, and HF (stable, symptomatic [New York Heart Association Class II or III] HF). Metoprolol selectively blocks the beta₁-adrenoreceptor (1). Beta-blockers are a recommended first-line therapy for cardiac conditions, including various arrhythmias, and as second-line therapy for hypertension by professional medical societies in the US and Europe (6, 7, 8).

There are 2 main types of adrenoreceptors, alpha and beta, each of which has numbered subtypes. The beta adrenoreceptors have 3 subtypes: beta₁, beta₂, and beta₃. All 3 subtypes are coupled to the G_s protein, which in turn activates adenylate cyclase, an enzyme that catalyzes the production of cyclic adenosine monophosphate (cAMP) from ATP. The binding of an agonist, such as the catecholamines adrenaline and noradrenaline, to beta receptors leads to a rise in the intracellular concentration of cAMP, which triggers signaling pathways via protein kinase A (9). Stimulation of the beta₁ receptor, which is predominantly expressed in cardiac tissue, leads to an increase in heart rate and the contractility of the atria and ventricles. It also leads to the increased secretion of hormones from other tissues, including renin (from the kidneys), ghrelin (from the stomach), and amylase (from the salivary glands).

Metoprolol exerts its therapeutic effects by reducing the impact of catecholamine stimulation. Metoprolol reduces heart rate, improves contractile function by stimulating the upregulation of beta₁ receptors, reduces vasoconstriction, and possibly also reduces the risk of arrhythmias (2, 10, 11, 12). In the treatment of HF, certain beta-blockers, such as extended-release metoprolol succinate, are thought to protect the heart from increased catecholamine stimulation. In the short term, adrenergic activation can help the heart maintain cardiac performance, but over time, continued activation can be detrimental. Harmful effects include a persistently increased heart rate, down-regulation and impaired functioning of the beta receptors, and myocyte hypertrophy and death, which lead to adverse remodeling of heart tissue (10, 13).

Metoprolol is a racemic mixture of R- and S-enantiomers (in equal amounts). S-metoprolol has a higher affinity for the beta₂ receptors than the R-enantiomer (14). R-metoprolol is predominantly metabolized by O-demethylation, whereas S-metoprolol primarily undergoes alpha-hydroxylation (15, 16, 17). Both pathways are metabolized extensively by CYP2D6, though CYP2D6 seems to metabolize R-metoprolol more efficiently (18). The CYP2D6 enzyme is absent in approximately 8% of Caucasians (PM) and approximately 2% of most other populations. Individuals who lack CYP2D6 activity will have plasma concentrations of metoprolol roughly 5 times higher and may be at an increased risk of side effects (18, 19, 20, 21). Individuals with hepatic or renal failure have also been reported to experience elevated plasma levels of metoprolol and increased exposure (22). Metoprolol has a relatively low (approximately 12%) albumin-bound fraction in plasma, can cross the blood-brain barrier, and shows a dose-related increase in bioavailability, though this increase is not directly proportional (1). At higher plasma concentrations, metoprolol is less cardioselective. Metoprolol can inhibit beta₂ receptors, which are mainly located in the bronchial and vascular musculature. The FDA-approved drug label advises that individuals with bronchospastic disease should not take beta-blockers, except for individuals who cannot tolerate another antihypertensive treatment; in such cases, the lowest possible dose should be used (1).

In a geriatric population, plasma levels of metoprolol above the median were associated with an increased risk of falls; however, this association was not seen for non-selective beta-blockers (23). The drug label in Canada and the FDA label for metoprolol tartrate recommend lower starting and maintenance doses, as well as safety monitoring in geriatric individuals on metoprolol therapy (24, 25).

The safety and effectiveness of metoprolol have not been established in individuals under 6 years of age, according to the FDA-approved label (1). Metoprolol has not been authorized for pediatric use in Canada (24). Even though beta-blockers are typically not recommended for use in pediatric individuals, off-label use in pediatric heart failure does occur (26). The few studies available provide conflicting outcomes regarding the benefit of beta-blockers in a pediatric HF population. Although this pharmacologic management approach did not appear to cause a significant rate of adverse events, more studies are needed to determine the efficacy of beta-blockers for pediatric HF (26). Much of the use of beta-blockers in a pediatric population is extrapolated from experiences in adults, and CPIC states that their recommendations can, with caution, be extrapolated from adult to pediatric use (4, 27). Changes in gene expression over the lifespan of an individual can impact drug responses; the primary metabolic enzyme for metoprolol, CYP2D6, is absent in fetal development but reaches mature expression within the first several post-natal weeks of life. Less is known regarding the beta-adrenergic receptors (27).

Metoprolol can cross the placenta and is secreted in breast milk (28). There are notable risks to a pregnant mother with untreated hypertension during pregnancy, including pre-eclampsia, gestational diabetes, premature delivery and delivery complications. Likewise, hypertension also increases the risk of adverse fetal outcomes (1). Observational studies have not definitively established nor excluded any drug-associated risk of major congenital malformations during pregnancy for metoprolol tartrate or succinate (1, 25). The combined levels of metoprolol and the alpha-OH-metoprolol metabolite secreted into breast milk are reported to be low (less than 2% of the mother’s weight-adjusted dose), and the amounts ingested by the infant are not expected to cause adverse effects, with studies to date finding no adverse reactions in breastfed infants (29). Changes in gene expression or metabolism can occur during pregnancy; an increase in the clearance rate of metoprolol has been reported during mid and late pregnancy, which may require changes in medication selection or dosing (30). However, the use of metoprolol during pregnancy or nursing is not recommended by Health Canada (24), and the US FDA advises monitoring of a breastfed infant for bradycardia or listlessness (signs of beta-blockade) (1).

Gene: CYP2D6

The CYP450s are a large and diverse group of enzymes that form the major system for metabolizing lipids, hormones, toxins, and drugs in the liver. The CYP450 genes are polymorphic and can result in decreased, absent, or increased enzyme activity. One prominent CYP450 member, CYP2D6, is responsible for the metabolism of many commonly prescribed drugs, including antidepressants, antipsychotics, analgesics, and beta-blockers.

Other Genes of Interest: ADRB1, ADRB2, OR10P1, SNX9, GRK5

The beta-adrenergic receptors mediate signaling via coupled G-protein signaling. In the heart, beta₁-adrenergic receptors are the primary target for beta-blockers and represent the major adrenergic receptor (27). Encoded by ADRB1 on chromosome 10q25, the beta₁-adrenergic receptor is a 7-transmembrane domain protein with intracellular and extracellular portions that facilitate ligand and G-protein binding (48, 49). Binding of a ligand to the receptor induces a conformational change that allows the G-alpha subunit to activate adenylyl cyclase, creating cAMP signaling molecules, which in turn leads to increased intracellular calcium ion levels. Calcium influx drives increased contractility and heart rate, as well as increased electrical automaticity (27).

There are known polymorphisms in ADRB1 that have been associated with disease and altered drug response in some studies. The 2 commonly studied variants are ADRB1 p.Ser49Gly (rs1801252, c.145A>G) and p.Arg389Gly (rs1801253, c.1165G>C). The p.389 residue falls within the G-protein binding intracellular loop, and the p.49 residue occurs in an extracellular loop (27). The C>G single nucleotide polymorphism (SNP) at rs1801253 (p.Arg389Gly) has been reported to occur at a frequency of 27% in individuals of European descent, 40–42% in those of African descent, 32–41% in individuals of Asian descent, and 19–32% in individuals of Latin American descent (50, 51). The variation at p.49 of ADRB1 (c.145A>G, rs1801252) occurs less frequently: 10–12.5% in Asian populations, 13% in European populations, 20–25% in African and African descent populations, and 17–24% in Latin American populations. These 2 variants are in negative linkage disequilibrium, such that it is unlikely for an individual to have a Gly49-Gly389 allele (27). Individuals homozygous for arginine at p.389 have been reported to have an increased risk of hypertension (50), and this variation may interact with other variants in the G-protein signaling pathway to negatively impact survival, particularly in individuals of African ancestry (52).

The beta₂-adrenergic receptor, encoded by ADRB2 and located on chromosome 5q32, has been associated with nocturnal asthma, obesity, type 2 diabetes, cardiovascular disease, and Parkinson’s disease risk (53). The ADRB2 protein is abundantly expressed in bronchial smooth muscle cells, where activation of the receptor leads to bronchodilation (54). It is also expressed, to a lesser extent, in the cardiac myocytes and vascular smooth muscle cells, contributing to increased heart rate and contractility following adrenergic stimulation (54). There are 2 common variants in ADRB2 that encode amino acid changes: rs1042713 (p.Gly16Arg) and rs1042714 (p.Glu27Gln, c.79G>C), with the minor allele frequencies ranging between 40–50% (54). The Gly16 protein isoform is more susceptible to agonist-stimulated downregulation in vitro (54). The Gln27 variant has been associated with increases in systolic blood pressure and reduced response to isoproterenol (54). A third variant, rs1800888 (p.Thr164Ile), is relatively rare, with a minor allele frequency range of ~1–2% in individuals of European or African ancestry, and it is not detected in Chinese populations (54). This rare allele is associated with reduced response to beta₂-agonists such as salmeterol or albuterol (54, 55).

A genome-wide association study found that OR10P1 and SNX9-linked variants were associated with changes in heart rate in response to beta-blocker therapy for individuals classified as ‘Black’ in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies (56). The variants g.56022983T>G (rs17117817, near the olfactory receptor family 10 subfamily-p-member 1 gene OR10P1) or rs2364349 c.1648+912G>A (rs2364349) (linked to the sorting nexin-9 gene SNX9) were associated with a decreased heart rate-lowering response in this population. These loci were found to yield significant association signals in ‘White’ study participants as well (56). There is evidence that OR10P1 is expressed in cardiac tissue and may indirectly interact with ADRB2, though the specific mechanism by which olfactory receptors impact heart rate is unknown. Sorting nexin-9 is associated with endocytosis of transmembrane signaling proteins and may be involved in regulating the endocytosis of ADRB2.

One study also found a connection between GRK5 variation and improved survival in HF. p.Gln41Leu (c.122A>T) in the G-protein-coupled receptor kinase 5 protein (rs17098707, now rs2230345) was reported to be more common in individuals of African ancestry than in Caucasians and may attenuate beta-adrenergic signaling, similar to beta-blocker medication (57). This same allele was examined in a Chinese population with an allele frequency of 0.008, but it was not associated with differences in systolic HF mortality compared with the reference allele (58).

Linking CYP2D6 and ADRB1/2 Genetic Variation with Treatment Response

Genetic variants of the CYP2D6 gene have been found to influence the ratio of enantiomers, the dose and dose titration of metoprolol, and heart rate—CYP2D6 PM have an increased risk of bradycardia (59, 60, 61, 62, 63, 64). However, in one study, CYP2D6 did not appear to influence the efficacy of metoprolol when used to treat hypertension (65). Reduced function of CYP2D6 enzyme alters the pharmacokinetics of metoprolol, resulting in increased exposure (measured by plasma area under the concentration-time curve levels) in PMs and IMs (*10/*10) and this is correlated with a higher risk of bradycardia in PMs (66). In a genome-wide association biobank study using ‘white’ (self-reported) study participants, metoprolol and alpha-OH-metoprolol concentrations were significantly associated with genetic variation located only in the CYP2D6 locus (67).

A meta-analysis of 21 studies reported a significant difference in the BP-lowering effects of metoprolol between CYP2D6 PMs and all other phenotypes (68). At similar doses, individuals with a PM CYP2D6 phenotype experienced a larger decrease in heart rate (measured in beats per minute, BPM), blood pressure (both systolic and diastolic), and more cases of bradycardia (heart rate of less than 60 BPM) across the relevant studies (68).

Variants within the beta₁ receptor have also been found to influence the treatment response to specific beta-blockers. The most studied is a reduced-function variant, p.Gly389Arg (rs1801253), which leads to reduced levels of cAMP and diminished beta₁ receptor signaling cascades (69). Individuals who are homozygous p.Arg389 may have a more favorable response to metoprolol treatment than individuals who are homozygous for the reference sequence p.Gly389 (69, 70, 71, 72, 73). The p.Ser49Gly (rs1801252) variant has been reported to be associated with increased ventricular ectopic beats and favorable beta-blocker response in a cohort study of hypertrophic cardiomyopathy (HCM), though the p.Gly389Arg polymorphism did not show significant impacts on beta-blocker response in this HCM cohort (74). The ADRB1 p.Gly389Arg (rs1801253) variant, which was associated with decreased response to beta-blockers, was detected in roughly half the cohort from the Alabama Genomic Health Initiative that had a prescription for one of the affected medicines, including metoprolol (75). One study found that individuals with HF and a variant allele (p.389Arg) at rs1801253 benefited from higher doses of beta-blockers (76). In a separate study, p.389Arg homozygous individuals had greater improvement in left ventricular ejection fraction compared with individuals with the homozygous reference allele (77). However, the CPIC guideline writing committee found the data insufficient to issue recommendations regarding genetic variations in ADRB1 and beta-blocker therapy, citing a need for additional research to refute or confirm the reported findings to date (4).

Additional studies have examined the role of beta₂ receptor variants and heart rate responses to beta-blockers (78). The PEAR-2 trial examined variants in metoprolol response for individuals with hypertension, finding a significant association of a more pronounced heart rate-lowering response with ADRB2 rs1042714 C/C genotype (encoding Gln at p.27) and a “trending toward significant” association with rs1042713 A-allele in ADRB2 (78). In contrast, the p.27Glu genotype was associated with longer survival for individuals with HF who were taking beta-blockers, and no association was observed with the p.Arg16Gly variants and clinical outcomes (76). This literature was also insufficient to justify clinical recommendations from the CPIC writing committee for beta-blockers and ADRB2 variation (4).

Other studies have failed to find associations between ADRB1 or ADRB2 common variants and blood pressure responses to beta-blockers (79), though it is unclear if the underlying cardiac disorder may impact the specific drug response (or lack of response) associated with genetic variants.

Genetic Testing

The NIH’s Genetic Testing Registry provides examples of the genetic tests available for metoprolol response and the CYP2D6 gene.

The available CYP2D6 tests include targeted single-gene tests as well as multi-gene panels. In addition, variant CYP2D6 alleles to be included in clinical genotyping assays have been recommended by the Association for Molecular Pathology (AMP) (80). For CYP2D6, the AMP recommends that the minimum panel of variant alleles should include *2, *3, *4, *5, *6, *9, *10, *17, *29, *41, and a copy number interrogation. Results are reported as a diplotype, such as CYP2D6 *1/*1; however, copy number testing is crucial when interpreting CYP2D6 results (81). When individuals have more than 2 copies of CYP2D6, the copies of the allele are denoted by an “xN”, where the “N” can either be quantified or unquantified (for example, CYP2D6 *1/*2x2 or CYP2D6 *1/*2xN). Some laboratories also use the notation of duplication (“DUP”) to indicate an increase in copy number, but the report does not always specify the number of duplications or the allele that has been duplicated due to technical limitations. The test results may include an interpretation of the individual’s predicted metabolizer phenotype, which can be confirmed by checking the diplotype and calculating the CYP2D6 activity score, as described in the “CYP2D6 Alleles” section above.

Multiple studies have reported successful implementation of pharmacogenetic testing to guide medication selection or dosing in real-world clinical settings (82, 83, 84). Of particular concern are cases where individuals are prescribed multiple medications for chronic health conditions, where gene-drug or gene-drug-drug interactions may negatively impact the individual’s response to medications (85).

The CYP2D6 Gene Interactions with Medications Used for Additional Indications

The CYP family of enzymes is involved in the metabolism of many substances, and CYP2D6 has been implicated in altered pharmacologic responses for many compounds. The drugs can be categorized into many different classes:

● Antipsychotics—for example, aripiprazole, risperidone, and thioridazine, and to a lesser extent, clozapine, are metabolized by CYP2D6. According to the FDA, aripiprazole dosage should be reduced for PMs, and thioridazine is contraindicated for individuals known to have reduced CYP2D6 activity due to an increased risk of potentially fatal side effects. The UMs may have a decreased plasma concentration of risperidone.

● Tricyclic antidepressants—for example, amitriptyline and imipramine may require dosage adjustments, potentially guided by therapeutic drug monitoring, to achieve the desired therapeutic range in UMs or PMs. Ultimately, tricyclic antidepressants may be ineffective in CYP2D6 UMs.

● Serotonin and norepinephrine reuptake inhibitors, for example atomoxetine and venlafaxine may have reduced efficacy in UMs at standard doses, while PMs are at risk of elevated plasma concentrations for both medications. The DPWG advises against the use of venlafaxine in CYP2D6 PMs and IMs.

● Antimalarial medications—for example, primaquine is activated by CYP2D6 and CYP450 Nicotinamide Adenine Dinucleotide Phosphate oxidoreductase.

● Anticancer medications—for example, tamoxifen is activated by CYP2D6, and IMs or PMs may have reduced benefit from tamoxifen therapy.

● Pain management—for example, codeine and tramadol are pro-drugs that require activation by CYP2D6 to achieve the desired analgesic effect.

● Various therapies for genetic disorders, for example, eliglustat used in the treatment of Gaucher disease, and deutetrabenazine, used in the treatment of Huntington disease, have reduced dose recommendations for CYP2D6 PMs. The CYP2D6 UMs may not achieve adequate concentrations of eliglustat, and therefore CYP2D6 genotyping is required before initiating eliglustat therapy.

It is important to note that CYP2D6 is the most common biomarker in drug responses for FDA drug labels. The lists provided here is by no means exhaustive. Additional information on gene-drug interactions for CYP2D6 is available from PharmGKB, CPIC, and the FDA (search for “CYP2D6”).

Therapeutic Recommendations based on Genotype

This section contains excerpted¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2024 Statement from the US Food and Drug Administration (FDA):

CYP2D6 Inhibitors are likely to increase metoprolol concentration. […] Drugs that are strong inhibitors of CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone were shown to double metoprolol concentrations. While there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. Increases in plasma concentration decrease the cardioselectivity of metoprolol … Monitor patients closely when the combination cannot be avoided.

[…]

Drug Interactions

CYP2D6

Metoprolol is metabolized predominantly by CYP2D6. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg, a potent CYP2D6 inhibitor, and immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life.

[…]

CYP2D6 is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by several drugs. Poor metabolizers of CYP2D6 will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity.

Please review the complete therapeutic recommendations that are located here: (1)

2024 Summary of recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC):

The evidence supporting the association of CYP2D6 genotype with metoprolol exposure and response included participants with a variety of health statuses (e.g., healthy, hypertension, heart failure, etc.). Therefore, it may be reasonable to assume that the pharmacokinetic effects of CYP2D6 variation would affect clinical metoprolol response similarly across a variety of indications, and the dosing recommendations provided could be utilized for most cardiovascular indications …

Recommendations primarily focus on minimizing the risk of adverse effects in CYP2D6 poor metabolizers related to the greater observed reductions in heart rate and blood pressure stemming from increased metoprolol systemic exposure. In addition, the maximally tolerated metoprolol dose may be lower in poor metabolizers compared with normal metabolizers due to these pharmacokinetic differences… We found insufficient evidence to support recommendations related to CYP2D6 genotype and other clinical outcomes.

While the evidence suggests metoprolol plasma concentrations are also increased in CYP2D6 intermediate metabolizers compared with normal metabolizers, these effects appear smaller in magnitude than those observed with poor metabolizers, and there was insufficient evidence to clarify whether these smaller pharmacokinetic differences significantly affect clinical response.

… Most of the data available regarding associations between CYP2D6 genotype and metoprolol response are related to oral formulations; limited evidence exists regarding pharmacogenetic effects with intravenous formulations.

….

CYP2D6 normal and intermediate metabolizers: Recommendations: Initiate standard dosing.

CYP2D6 poor metabolizers: Recommendations: Initiate therapy with lowest recommended starting dose. Carefully titrate dose upward to clinical effect or guideline-recommended dose; monitor more closely for bradycardia. Alternatively, consider selecting another beta-blocker.

CYP2D6 ultrarapid metabolizers: No recommendation for metoprolol therapy due to insufficient evidence regarding diminished metoprolol effectiveness clinically.

Please review the complete therapeutic recommendations that are located here: (4)

2022 Summary of recommendations from the Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy (KNMP):

CYP2D6 Poor Metabolizers:

The gene variation reduces the conversion of metoprolol to inactive metabolites. However, the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia.

Recommendation:

If a gradual reduction in heart rate is desired, or in the event of symptomatic bradycardia:

1. Use smaller steps in dose titration and/or prescribe no more than 25% of the standard dose

Other cases:

1.

No action required

CYP2D6 Intermediate Metabolizers:

The gene variation reduces the conversion of metoprolol to inactive metabolites. However, the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia.

Recommendation:

If a gradual reduction in heart rate is desired, or in the event of symptomatic bradycardia:

1. Use smaller steps in dose titration and/or prescribe no more than 50% of the standard dose.

Other cases:

1. No action required

CYP2D6 Ultrarapid Metabolizers:

The gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate.

Recommendation:

1. Use the maximum dose for the relevant indication as a target dose

2. If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative

Possible alternatives include:

• Heart failure: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6.
• Other indications: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

Please review the complete therapeutic recommendations that are located here: (5)

Nomenclature of Selected CYP2D6 Alleles

Nomenclature of Selected ADRB1 Alleles

Nomenclature of Selected ADRB2 Alleles

Acknowledgments

2024 Edition: (v2.0)

The author would like to thank Jordan Baye, PharmD, MA, BCPS, Associate Professor, College of Pharmacy and Allied Health Professions, South Dakota State University, Sioux Falls, SD, USA; Maxime Meloche-Brouillette, PhD, Research Associate, Montreal Heart Institute, and Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada; Marga Nijenhuis, PhD, Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands; and Mollie M. Walton, MD, Pediatric Cardiologist and Clinical Pharmacology Fellow, Pediatric Cardiology, Children’s Mercy, Kansas City, MO, USA for reviewing this summary.

2017 Edition (Published April 4, 2017, v1.0):

The author would like to thank Larisa H. Cavallari, PharmD, Associate Professor, Department of Pharmacotherapy and Translational Research & Director, Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA; Mandy van Rhenen, secretary of the Dutch Pharmacogenetics Working Group (DPWG), Centre for Information on Medicines, Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands; and John Wikstrand, Professor of Clinical Physiology, Wallenberg Laboratory, University of Gothenburg, Sweden, for reviewing this summary.

Version History

The April 4, 2017 version (1.0) of this chapter is available as a PDF here.

Version 2.0 published on September 19, 2024 encompasses new recommendations from CPIC that were not previously available as well as expanded recommendations from DPWG that include dosing adjustment guidelines for CYP2D6 IM and UM individuals. Language from the FDA-approved drug label discussing drug-drug interactions via CYP metabolism is also included in version 2.0. Updated CYP2D6 allele information, activity scores and translation from genotype-based activity scores to predicted metabolizer phenotype are also provided in this version based on harmonized international standards. The Genetic Testing section also includes the recommendations from AMP regarding Tier 1 and Tier 2 alleles for CYP2D6 pharmacogenetic testing.

References

1.

Metoprolol succinate Piscataway, NJ, USA: Camber Pharmaceuticals Inc.; 2024. Available from: https://dailymed​.nlm​.nih.gov/dailymed/drugInfo​.cfm?setid=74a28333-53c1-493e-b6ad-2192fdc35391.

2.

Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet, 1999. 353(9169): p. 2001-7. [PubMed: 10376614]

3.

Kotecha, D., L. Manzano, H. Krum, G. Rosano, et al., Effect of age and sex on efficacy and tolerability of beta blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis. BMJ, 2016. 353: p. i1855. [PMC free article: PMC4849174] [PubMed: 27098105]

4.

Duarte, J.D., C.D. Thomas, C.R. Lee, R. Huddart, et al., Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta-Blocker Therapy. Clin Pharmacol Ther, 2024. [PubMed: 38951961]

5.

Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines [Internet]. Netherlands. Metoprolol – CYP2D6 [Cited May 2024]. Available from https://www​.knmp.nl/dossiers​/farmacogenetica.

6.

Whelton, P.K., R.M. Carey, W.S. Aronow, D.E. Casey, Jr., et al., 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension, 2018. 71(6): p. e13-e115. [PubMed: 29133356]

7.

Williams, B., G. Mancia, W. Spiering, E. Agabiti Rosei, et al., 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens, 2018. 36(10): p. 1953-2041. [PubMed: 30234752]

8.

Mancia, G., S.E. Kjeldsen, R. Kreutz, A. Pathak, et al., Individualized Beta-Blocker Treatment for High Blood Pressure Dictated by Medical Comorbidities: Indications Beyond the 2018 European Society of Cardiology/European Society of Hypertension Guidelines. Hypertension, 2022. 79(6): p. 1153-1166. [PubMed: 35378981]

9.

Whirl-Carrillo, M., R. Huddart, L. Gong, K. Sangkuhl, et al., An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine. Clin Pharmacol Ther, 2021. 110(3): p. 563-572. [PMC free article: PMC8457105] [PubMed: 34216021]

10.

Bristow, M.R., beta-adrenergic receptor blockade in chronic heart failure. Circulation, 2000. 101(5): p. 558-69. [PubMed: 10662755]

11.

Yoshikawa, T., S. Handa, T. Anzai, H. Nishimura, et al., Early reduction of neurohumoral factors plays a key role in mediating the efficacy of beta-blocker therapy for congestive heart failure. Am Heart J, 1996. 131(2): p. 329-36. [PubMed: 8579029]

12.

Gilbert, E.M., W.T. Abraham, S. Olsen, B. Hattler, et al., Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation, 1996. 94(11): p. 2817-25. [PubMed: 8941107]

13.

Sackner-Bernstein, J.D. and D.M. Mancini, Rationale for treatment of patients with chronic heart failure with adrenergic blockade. JAMA, 1995. 274(18): p. 1462-7. [PubMed: 7474194]

14.

Cerqueira, P.M., E.J. Cesarino, F.H. Mateus, Y. Mere, Jr., et al., Enantioselectivity in the steady-state pharmacokinetics of metoprolol in hypertensive patients. Chirality, 1999. 11(7): p. 591-7. [PubMed: 10423287]

15.

Murthy, S.S., H.U. Shetty, W.L. Nelson, P.R. Jackson, and M.S. Lennard, Enantioselective and diastereoselective aspects of the oxidative metabolism of metoprolol. Biochem Pharmacol, 1990. 40(7): p. 1637-44. [PubMed: 2222517]

16.

Antunes Nde, J., R.C. Cavalli, M.P. Marques, E.C. Moises, and V.L. Lanchote, Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients. Br J Clin Pharmacol, 2015. 79(4): p. 605-16. [PMC free article: PMC4386945] [PubMed: 25291152]

17.

Borg, K.O., E. Carlsson, K.J. Hoffmann, T.E. Jonsson, et al., Metabolism of metoprolol-(3-h) in man, the dog and the rat. Acta Pharmacol Toxicol (Copenh), 1975. 36(Suppl 5): p. 125-35. [PubMed: 1079685]

18.

Blake, C.M., E.D. Kharasch, M. Schwab, and P. Nagele, A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics. Clin Pharmacol Ther, 2013. 94(3): p. 394-9. [PMC free article: PMC3818912] [PubMed: 23665868]

19.

Rau, T., H. Wuttke, L.M. Michels, U. Werner, et al., Impact of the CYP2D6 genotype on the clinical effects of metoprolol: a prospective longitudinal study. Clin Pharmacol Ther, 2009. 85(3): p. 269-72. [PubMed: 19037197]

20.

Jin, S.K., H.J. Chung, M.W. Chung, J.I. Kim, et al., Influence of CYP2D6*10 on the pharmacokinetics of metoprolol in healthy Korean volunteers. J Clin Pharm Ther, 2008. 33(5): p. 567-73. [PubMed: 18834373]

21.

Wuttke, H., T. Rau, R. Heide, K. Bergmann, et al., Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects. Clin Pharmacol Ther, 2002. 72(4): p. 429-37. [PubMed: 12386645]

22.

Zamir, A., I. Hussain, A. Ur Rehman, W. Ashraf, et al., Clinical Pharmacokinetics of Metoprolol: A Systematic Review. Clin Pharmacokinet, 2022. 61(8): p. 1095-1114. [PubMed: 35764772]

23.

Ploegmakers, K.J., E.P. van Poelgeest, L.J. Seppala, S.C. van Dijk, et al., The role of plasma concentrations and drug characteristics of beta-blockers in fall risk of older persons. Pharmacol Res Perspect, 2023. 11(6): p. e01126. [PMC free article: PMC10603288] [PubMed: 37885367]

24.

PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION, AA-METOPROLOL SR. Vaughan, Ontario, Canada: AA Pharma Inc.; 2022. Available from: https://pdf​.hres.ca/dpd_pm/00067786.PDF.

25.

METOPROLOL TARTRATE- metoprolol tablet. Inc., A.P.; 2024. Available from: https://dailymed​.nlm​.nih.gov/dailymed/drugInfo​.cfm?setid=24837d82-0f3f-4482-9af0-31e5f675c30f.

26.

Alabed, S., A. Sabouni, S. Al Dakhoul, and Y. Bdaiwi, Beta-blockers for congestive heart failure in children. Cochrane Database Syst Rev, 2020. 7(7): p. CD007037. [PMC free article: PMC7389334] [PubMed: 32700759]

27.

Walton, M. and J.B. Wagner, Pediatric Beta Blocker Therapy: A Comprehensive Review of Development and Genetic Variation to Guide Precision-Based Therapy in Children, Adolescents, and Young Adults. Genes (Basel), 2024. 15(3). [PMC free article: PMC10969836] [PubMed: 38540438]

28.

Gaedigk, A., S.T. Casey, M. Whirl-Carrillo, N.A. Miller, and T.E. Klein, Pharmacogene Variation Consortium: A Global Resource and Repository for Pharmacogene Variation. Clin Pharmacol Ther, 2021. 110(3): p. 542-545. [PMC free article: PMC8725060] [PubMed: 34091888]

29.

Metoprolol, in Drugs and Lactation Database (LactMed(R)). 2006: Bethesda (MD). Available from https://www​.ncbi.nlm​.nih.gov/pubmed/30000215.

30.

Ryu, R.J., S. Eyal, T.R. Easterling, S.N. Caritis, et al., Pharmacokinetics of metoprolol during pregnancy and lactation. J Clin Pharmacol, 2016. 56(5): p. 581-9. [PMC free article: PMC5564514] [PubMed: 26461463]

31.

Nofziger, C., A.J. Turner, K. Sangkuhl, M. Whirl-Carrillo, et al., PharmVar GeneFocus: CYP2D6. Clin Pharmacol Ther, 2020. 107(1): p. 154-170. [PMC free article: PMC6925641] [PubMed: 31544239]

32.

Gaedigk, A., M. Ingelman-Sundberg, N.A. Miller, J.S. Leeder, et al., The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database. Clin Pharmacol Ther, 2018. 103(3): p. 399-401. [PMC free article: PMC5836850] [PubMed: 29134625]

33.

Caudle, K.E., H.M. Dunnenberger, R.R. Freimuth, J.F. Peterson, et al., Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med, 2017. 19(2): p. 215-223. [PMC free article: PMC5253119] [PubMed: 27441996]

34.

CYP2D6 allele functionality table [Cited 6 June 2024]. Available from https://api​.pharmgkb​.org/v1/download/file​/attachment/CYP2D6_allele​_functionality_reference.xlsx.

35.

Yokota, H., S. Tamura, H. Furuya, S. Kimura, et al., Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism. Pharmacogenetics, 1993. 3(5): p. 256-63. [PubMed: 8287064]

36.

Ingelman-Sundberg, M., Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J, 2005. 5(1): p. 6-13. [PubMed: 15492763]

37.

PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*4 [Cited 26 Sept 2016]. Available from https://www​.pharmgkb​.org/haplotype/PA165816579.

38.

PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*10 [Cited 26 Sept 2016]. Available from https://www​.pharmgkb​.org/haplotype/PA165816582.

39.

Bradford, L.D., CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics, 2002. 3(2): p. 229-43. [PubMed: 11972444]

40.

PharmVar. CYP2D6. 2024 [cited 2024; Available from: https://www​.pharmvar.org/gene/CYP2D6.

41.

US FDA. Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers. 2023 5 June 2023 7 June 2024]; Available from: https://www​.fda.gov/drugs​/drug-interactions-labeling​/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.

42.

Smith, D.M., K.W. Weitzel, A.R. Elsey, T. Langaee, et al., CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial. Genet Med, 2019. 21(8): p. 1842-1850. [PMC free article: PMC6650382] [PubMed: 30670877]

43.

Monte, A.A., K. West, K.T. McDaniel, H.K. Flaten, et al., CYP2D6 Genotype Phenotype Discordance Due to Drug-Drug Interaction. Clin Pharmacol Ther, 2018. 104(5): p. 933-939. [PMC free article: PMC6197912] [PubMed: 29882961]

44.

Patel, J.N., S.A. Morris, R. Torres, B. Rhead, et al., Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients. Mol Psychiatry, 2024. [PubMed: 38783055]

45.

den Uil, M.G., H.W. Hut, K.R. Wagelaar, H. Abdullah-Koolmees, et al., Pharmacogenetics and phenoconversion: the influence on side effects experienced by psychiatric patients. Front Genet, 2023. 14: p. 1249164. [PMC free article: PMC10486269] [PubMed: 37693320]

46.

Robert, S., M.O. Pilon, E. Oussaid, M. Meloche, et al., Impact of amiodarone use on metoprolol concentrations, alpha-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study. Pharmacol Res Perspect, 2023. 11(5): p. e01137. [PMC free article: PMC10512912] [PubMed: 37732835]

47.

Cicali, E.J., A.L. Elchynski, K.J. Cook, J.T. Houder, et al., How to Integrate CYP2D6 Phenoconversion Into Clinical Pharmacogenetics: A Tutorial. Clin Pharmacol Ther, 2021. 110(3): p. 677-687. [PMC free article: PMC8404400] [PubMed: 34231197]

48.

Yang-Feng, T.L., F.Y. Xue, W.W. Zhong, S. Cotecchia, et al., Chromosomal organization of adrenergic receptor genes. Proc Natl Acad Sci U S A, 1990. 87(4): p. 1516-20. [PMC free article: PMC53506] [PubMed: 2154750]

49.

Frielle, T., S. Collins, K.W. Daniel, M.G. Caron, et al., Cloning of the cDNA for the human beta 1-adrenergic receptor. Proc Natl Acad Sci U S A, 1987. 84(22): p. 7920-4. [PMC free article: PMC299447] [PubMed: 2825170]

50.

Dorn, G.W., 2nd, Adrenergic signaling polymorphisms and their impact on cardiovascular disease. Physiol Rev, 2010. 90(3): p. 1013-62. [PubMed: 20664078]

51.

Reference SNP (rs) Report rs1801253 [Cited 2024]. Available from https://www​.ncbi.nlm​.nih.gov/snp/rs1801253.

52.

Johnson, A.E., K. Hanley-Yanez, C.W. Yancy, A.L. Taylor, et al., Adrenergic Polymorphisms and Survival in African Americans With Heart Failure: Results From A-HeFT. J Card Fail, 2019. 25(7): p. 553-560. [PMC free article: PMC6660412] [PubMed: 30978507]

53.

ADRB2 adrenoreceport beta 2 [Homo sapiens (human)]. Gene 2 May 2024 [cited 2024; Available from: https://www​.ncbi.nlm.nih.gov/gene/154.

54.

Litonjua, A.A., L. Gong, Q.L. Duan, J. Shin, et al., Very important pharmacogene summary ADRB2. Pharmacogenet Genomics, 2010. 20(1): p. 64-9. [PMC free article: PMC3098753] [PubMed: 19927042]

55.

Leineweber, K. and G. Heusch, Beta 1- and beta 2-adrenoceptor polymorphisms and cardiovascular diseases. Br J Pharmacol, 2009. 158(1): p. 61-9. [PMC free article: PMC2795234] [PubMed: 19422376]

56.

Shahin, M.H., D.J. Conrado, D. Gonzalez, Y. Gong, et al., Genome-Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to beta-Blockers. J Am Heart Assoc, 2018. 7(5). [PMC free article: PMC5866313] [PubMed: 29478026]

57.

Liggett, S.B., S. Cresci, R.J. Kelly, F.M. Syed, et al., A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med, 2008. 14(5): p. 510-7. [PMC free article: PMC2596476] [PubMed: 18425130]

58.

Kang, S., X. Hong, C.W. Ruan, P. Yu, et al., Effects of GRK5 and ADRB1 polymorphisms influence on systolic heart failure. J Transl Med, 2015. 13: p. 44. [PMC free article: PMC4345005] [PubMed: 25638254]

59.

Baudhuin, L.M., W.L. Miller, L. Train, S. Bryant, et al., Relation of ADRB1, CYP2D6, and UGT1A1 polymorphisms with dose of, and response to, carvedilol or metoprolol therapy in patients with chronic heart failure. Am J Cardiol, 2010. 106(3): p. 402-8. [PubMed: 20643254]

60.

Batty, J.A., A.S. Hall, H.L. White, J. Wikstrand, et al., An investigation of CYP2D6 genotype and response to metoprolol CR/XL during dose titration in patients with heart failure: a MERIT-HF substudy. Clin Pharmacol Ther, 2014. 95(3): p. 321-30. [PubMed: 24193112]

61.

Hamadeh, I.S., T.Y. Langaee, R. Dwivedi, S. Garcia, et al., Impact of CYP2D6 polymorphisms on clinical efficacy and tolerability of metoprolol tartrate. Clin Pharmacol Ther, 2014. 96(2): p. 175-81. [PMC free article: PMC4111800] [PubMed: 24637943]

62.

Bijl, M.J., L.E. Visser, R.H. van Schaik, J.A. Kors, et al., Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users. Clin Pharmacol Ther, 2009. 85(1): p. 45-50. [PubMed: 18784654]

63.

Collett, S., A. Massmann, N.J. Petry, J. Van Heukelom, et al., Metoprolol and CYP2D6: A Retrospective Cohort Study Evaluating Genotype-Based Outcomes. J Pers Med, 2023. 13(3). [PMC free article: PMC10058912] [PubMed: 36983598]

64.

Huang, J., S.K. Chuang, C.L. Cheng, and M.L. Lai, Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes. Clin Pharmacol Ther, 1999. 65(4): p. 402-7. [PubMed: 10223777]

65.

Zineh, I., A.L. Beitelshees, A. Gaedigk, J.R. Walker, et al., Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension. Clin Pharmacol Ther, 2004. 76(6): p. 536-44. [PubMed: 15592325]

66.

Lee, C.M., P. Kang, C.K. Cho, H.J. Park, et al., Physiologically based pharmacokinetic modelling to predict the pharmacokinetics of metoprolol in different CYP2D6 genotypes. Arch Pharm Res, 2022. 45(6): p. 433-445. [PubMed: 35763157]

67.

Laverdiere, J., M. Meloche, S. Provost, G. Leclair, et al., Pharmacogenomic markers of metoprolol and alpha-OH-metoprolol concentrations: a genome-wide association study. Pharmacogenomics, 2023. 24(8): p. 441-448. [PubMed: 37307170]

68.

Meloche, M., M. Khazaka, I. Kassem, A. Barhdadi, et al., CYP2D6 polymorphism and its impact on the clinical response to metoprolol: A systematic review and meta-analysis. Br J Clin Pharmacol, 2020. 86(6): p. 1015-1033. [PMC free article: PMC7256128] [PubMed: 32090368]

69.

Parvez, B., N. Chopra, S. Rowan, J.C. Vaglio, et al., A common beta1-adrenergic receptor polymorphism predicts favorable response to rate-control therapy in atrial fibrillation. J Am Coll Cardiol, 2012. 59(1): p. 49-56. [PMC free article: PMC3245828] [PubMed: 22192668]

70.

Lymperopoulos, A. and A. Bathgate, Pharmacogenomics of the heptahelical receptor regulators G-protein-coupled receptor kinases and arrestins: the known and the unknown. Pharmacogenomics, 2012. 13(3): p. 323-41. [PubMed: 22304582]

71.

Huntgeburth, M., K. La Rosee, H. ten Freyhaus, M. Bohm, et al., The Arg389Gly beta1-adrenoceptor gene polymorphism influences the acute effects of beta-adrenoceptor blockade on contractility in the human heart. Clin Res Cardiol, 2011. 100(8): p. 641-7. [PubMed: 21311897]

72.

Liu, J., Z.Q. Liu, Z.R. Tan, X.P. Chen, et al., Gly389Arg polymorphism of beta1-adrenergic receptor is associated with the cardiovascular response to metoprolol. Clin Pharmacol Ther, 2003. 74(4): p. 372-9. [PubMed: 14534524]

73.

Chen, L., T. Xiao, L. Chen, S. Xie, et al., The Association of ADRB1 and CYP2D6 Polymorphisms With Antihypertensive Effects and Analysis of Their Contribution to Hypertension Risk. Am J Med Sci, 2018. 355(3): p. 235-239. [PubMed: 29549925]

74.

Raimoglou, D., C. Izgi, R. Enar, M.H. Karpuz, et al., Structural and Functional Impact of Adrenoceptor Beta-1 Gene Polymorphism in Patients with Hypertrophic Cardiomyopathy and Response to Beta-Blocker Therapy. Anatol J Cardiol, 2024. 28(3): p. 150-157. [PMC free article: PMC10918278] [PubMed: 38419512]

75.

Davis, B.H., K. Williams, D. Absher, B. Korf, and N.A. Limdi, Evaluation of population-level pharmacogenetic actionability in Alabama. Clin Transl Sci, 2021. 14(6): p. 2327-2338. [PMC free article: PMC8604228] [PubMed: 34121327]

76.

Guerra, L.A., C. Lteif, M.J. Arwood, C.W. McDonough, et al., Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking beta-blockers. Pharmacogenomics J, 2022. 22(1): p. 62-68. [PMC free article: PMC8799480] [PubMed: 34642472]

77.

Terra, S.G., K.K. Hamilton, D.F. Pauly, C.R. Lee, et al., Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy. Pharmacogenet Genomics, 2005. 15(4): p. 227-34. [PubMed: 15864115]

78.

Shahin, M.H., N.E. Rouby, D.J. Conrado, D. Gonzalez, et al., beta(2) -Adrenergic Receptor Gene Affects the Heart Rate Response of beta-Blockers: Evidence From 3 Clinical Studies. J Clin Pharmacol, 2019. 59(11): p. 1462-1470. [PMC free article: PMC6773496] [PubMed: 31090079]

79.

Suonsyrja, T., K. Donner, T. Hannila-Handelberg, H. Fodstad, et al., Common genetic variation of beta1- and beta2-adrenergic receptor and response to four classes of antihypertensive treatment. Pharmacogenet Genomics, 2010. 20(5): p. 342-5. [PubMed: 20300048]

80.

Pratt, V.M., L.H. Cavallari, A.L. Del Tredici, A. Gaedigk, et al., Recommendations for Clinical CYP2D6 Genotyping Allele Selection: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and European Society for Pharmacogenomics and Personalized Therapy. J Mol Diagn, 2021. [PMC free article: PMC8579245] [PubMed: 34118403]

81.

Hicks, J.K., J.R. Bishop, K. Sangkuhl, D.J. Muller, et al., Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther, 2015. 98(2): p. 127-34. [PMC free article: PMC4512908] [PubMed: 25974703]

82.

O'Shea, J., M. Ledwidge, J. Gallagher, C. Keenan, and C. Ryan, Pharmacogenetic interventions to improve outcomes in patients with multimorbidity or prescribed polypharmacy: a systematic review. Pharmacogenomics J, 2022. 22(2): p. 89-99. [PMC free article: PMC8975737] [PubMed: 35194175]

83.

Hayashi, M., D.A. Hamdy, and S.H. Mahmoud, Applications for pharmacogenomics in pharmacy practice: A scoping review. Res Social Adm Pharm, 2022. 18(7): p. 3094-3118. [PubMed: 34474980]

84.

Swen, J.J., C.H. van der Wouden, L.E. Manson, H. Abdullah-Koolmees, et al., A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study. Lancet, 2023. 401(10374): p. 347-356. [PubMed: 36739136]

85.

Hjemas, B.J., K. Bovre, K. Bjerknes, L. Mathiesen, et al., Implementation of pharmacogenetic testing in medication reviews in a hospital setting. Br J Clin Pharmacol, 2023. 89(10): p. 3116-3125. [PubMed: 37277227]