Clinical Pharmacogenomics of Carvedilol: the Stereo-Selective Metabolism Angle

Parker, Barbara M; Rogers, Sara; Lymperopoulos, Anastasios

doi:10.2217/pgs-2018-0115

Cited by 11 publications

(3 citation statements)

References 18 publications

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“…CYP2D6 metabolizes up to 25% of drugs commonly used in clinical practice. It is the enzyme primarily responsible for metabolizing the β-blocker carvedilol (Parker et al, 2018 ). Carvedilol, which is used to treat hypertension and heart disease, was co-prescribed to 10% of Zimbabwean participants on warfarin treatment.…”

Section: Discussionmentioning

confidence: 99%

Warfarin Pharmacogenomics for Precision Medicine in Real-Life Clinical Practice in Southern Africa: Harnessing 73 Variants in 29 Pharmacogenes

Muyambo

Ndadza

Soko

et al. 2022

OMICS: A Journal of Integrative Biology

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Pharmacogenomics is universally relevant for worldwide modern therapeutics and yet needs further development in resource-limited countries. While there is an abundance of genetic association studies in controlled medical settings, there is a paucity of studies with a naturalistic design in real-life clinical practice in patients with comorbidities and under multiple drug treatment regimens. African patients are often burdened with communicable and noncommunicable comorbidities, yet the application of pharmacogenomics in African clinical settings remains limited. Using warfarin as a model, this study aims at minimizing gaps in precision/personalized medicine research in African clinical practice. We present, therefore, pharmacogenomic profiles of a cohort of 503 black Africans ( n = 252) and Mixed Ancestry ( n = 251) patients from Southern Africa, on warfarin and co-prescribed drugs in a naturalized noncontrolled environment. Seventy-three ( n = 73) single nucleotide polymorphisms (SNPs) in 29 pharmacogenes were characterized using a combination of allelic discrimination, Sanger sequencing, restriction fragment length polymorphism, and Sequenom Mass Array. The common comorbidities were hypertension (43–46%), heart failure (39–45%), diabetes mellitus (18%), arrhythmia (25%), and HIV infection (15%). Accordingly, the most common co-prescribed drugs were antihypertensives, antiarrhythmic drugs, antidiabetics, and antiretroviral therapy. We observed marked variation in major pharmacogenes both at interethnic levels and within African subpopulations. The Mixed Ancestry group presented a profile of genetic variants reflecting their European, Asian, and African admixture. Precision medicine requires that African populations begin to capture their own pharmacogenetic SNPs as they cannot always infer with absolute certainty from Asian and European populations. In the current historical moment of the COVID-19 pandemic, we also underscore that the spectrum of drugs interacting with warfarin will likely increase, given the systemic and cardiovascular effects of COVID-19, and the anticipated influx of COVID-19 medicines in the near future. This observational clinical pharmacogenomics study of warfarin, together with past precision medicine research, collectively, lends strong support for incorporation of pharmacogenetic profiling in clinical settings in African patients for effective and safe administration of therapeutics.

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Section: Discussionmentioning

confidence: 99%

Warfarin Pharmacogenomics for Precision Medicine in Real-Life Clinical Practice in Southern Africa: Harnessing 73 Variants in 29 Pharmacogenes

Muyambo

Ndadza

Soko

et al. 2022

OMICS: A Journal of Integrative Biology

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“…Existence of various polymorphisms on both target receptors and metabolizing enzymes such as CYP2D6 cause variations in carvedilol serum level as well as its signaling effects, respectively, and hence influence clinical outcomes. 34,35 Measuring serum levels of carvedilol in both groups of HF patients along with genotyping of CYP2D6 may provide more vivid results in future studies.…”

Section: Discussionmentioning

confidence: 99%

<p>Biomarkers of IL-33 and sST2 and Lack of Association with Carvedilol Therapy in Heart Failure</p>

Firouzabadi¹,

Dashti²,

Dehshahri³

et al. 2020

CPAA

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Objective: The IL-33/ST2 pathway plays a fundamental role in the cardiovascular system and can be considered as a new therapeutic strategy for the treatment or prevention of cardiovascular diseases. ST2, as an interleukin (IL)-1 receptor family member, has transmembrane (ST2L) and soluble (sST2) isoforms. sST2 neutralizes IL-33 and thereby inhibits the cardioprotective role of IL-33/ST2L signaling pathway. Increase in sST2 level is associated with weak cardiac output and can be a predictor of mortality in heart failure (HF). Thereby, we hypothesized that there may be a relationship between the cardioprotective effects of carvedilol and sST2 and IL-3 in HF patients. Methods: sST2 and IL-33 were measured in serum of 66 individuals; 22 healthy volunteers and 44 suffering from HF; among whom 25 patients received carvedilol and the other 19 patients did not receive any β-blockers. Results: Lack of association between serum levels of IL-33 and sST2 was observed between HF patients and healthy individuals (2.4466 ± 0.69 vs 2.6748 ± 0.33 and 3416.6 ± 1089.1 vs 2971.6 ± 792.5, respectively). Our results indicated no significant difference between sST2 and IL-33 levels in HF patients who did not receive beta-blockers and patients receiving carvedilol (P=0.59 and P=0.97). Conclusion: Our results showed a lack of association between serum levels of IL-33 and sST2 and HF. Moreover, the results do not confirm the cardioprotective mechanism of carvedilol by means of IL-33/sST2 pathway.

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“…Regarding the lack of information on the cytochrome P450 2D6 polymorphisms in the study population, despite carvedilol is extensively metabolized by this enzyme 41,42 , to date, in Europe, none of the summaries of product characteristics of medicinal products containing carvedilol include polymorphisms of the gene codifying this enzyme as a “ contraindications ”/“ special warnings and precautions for use ” for its prescription. Therefore, we believe that even in the setting of poor, rapid or ultra-rapid metabolizers, it should not have influenced the prescription choice.…”

Section: Discussionmentioning

confidence: 99%

Beta-blocker choice and exchangeability in patients with heart failure and chronic obstructive pulmonary disease: an Italian register-based cohort study

Sessa

Mascolo

Rasmussen

et al. 2019

Sci Rep

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Clinical guidelines suggest that for patients with heart failure and concurrent chronic obstructive pulmonary disease (COPD), metoprolol/bisoprolol/nebivolol should be preferred over carvedilol. However, studies suggest a high proportion of carvedilol usage that remains unexplained. Therefore, we aimed to investigate the predictors of carvedilol choice in patients with heart failure and COPD that were naïve to carvedilol or metoprolol/bisoprolol/nebivolol. Caserta Local Health Unit databases (Italy) were used as data sources. Age, sex, chronic/acute comorbidities, and co-medications were included in a logistic regression model to assess predictors of carvedilol choice. Chronic comorbidities include those defined in the Elixhauser comorbidity index and all hospitalizations within two years prior to the first beta-blocker prescription. Comedications include all redeemed prescriptions within one year prior to the beta-blocker prescription. Kernel density estimations were used to assess the overlap in propensity and preference scores distributions for receiving carvedilol and thereby potential beta-blocker exchangeability. Totally, 10091 patients composed the study population; 2011 were exposed to carvedilol. The overlapping of propensity scores distributions was 57%. Accordingly, the exchangeability was not reached. Atrioventricular block (Odds Ratio, OR 8.20; 95% Confidence Interval, 95% CI 1.30–51.80), cerebrovascular thrombosis (OR 7.06; 95% CI 1.14–43.68), chronic kidney disease (OR 4.32; 95% CI 1.16–16.02), and acute heart failure (OR 1.97; 95% CI 1.28–3.03) hospitalizations were statistically significantly associated with carvedilol choice. Analogously, human insulin (OR 3.00; 95% CI 1.24–7.24), fondaparinux (OR 2.47; 95% CI 1.17–5.21) or strontium ranelate (OR 2.03; 95% CI 1.06–3.90) redeemed prescriptions. In conclusion, this study suggests the absence of beta-blockers exchangeability and a preferential choice of carvedilol in patients with heart failure, COPD and concurrent chronic kidney disease, atrioventricular block, cerebrovascular thrombosis, acute heart failure or redeeming human insulin, fondaparinux or strontium ranelate prescriptions. Therefore, it suggests that choice of prescribing carvedilol over metoprolol/bisoprolol/nebivolol is driven by differences in comorbidities and co-treatments.

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Clinical Pharmacogenomics of Carvedilol: the Stereo-Selective Metabolism Angle

Abstract: the three major enzymes/proteins carrying out carvedilol's stereo-selective metabolism are the highly polymorphic CYP2D6, UGT1 and P-glycoprotein. "

Cited by 11 publications

References 18 publications

Warfarin Pharmacogenomics for Precision Medicine in Real-Life Clinical Practice in Southern Africa: Harnessing 73 Variants in 29 Pharmacogenes

Warfarin Pharmacogenomics for Precision Medicine in Real-Life Clinical Practice in Southern Africa: Harnessing 73 Variants in 29 Pharmacogenes

<p>Biomarkers of IL-33 and sST2 and Lack of Association with Carvedilol Therapy in Heart Failure</p>

Beta-blocker choice and exchangeability in patients with heart failure and chronic obstructive pulmonary disease: an Italian register-based cohort study

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