A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials

Denus, Simon de; Rouleau, Jean L.; Mann, Douglas L.; Huggins, Gordon S.; Cappola, Thomas P.; Shah, Svati H.; Keleti, Julianna; Zada, Yassamin Feroz; Provost, Sylvie; Bardhadi, Amina; Phillips, Michael; Normand, Valérie; Mongrain, Ian; Dubé, Marie‐Pierre

doi:10.1038/tpj.2016.4

Cited by 12 publications

(12 citation statements)

References 42 publications

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“…MRP4 genetic polymorphism (g.33387C > A) has been shown to be associated with weight loss when furosemide is given in decompensated heart failure patients. 65 This finding together with our in vitro data indicates that the altered MRP4 function due to drug interactions, aging, and pathophysiological factors could alter the safety or efficacy of furosemide.…”

Section: Discussionsupporting

confidence: 56%

Contribution of Uptake and Efflux Transporters to Oral Pharmacokinetics of Furosemide

Chapa

Basit

et al. 2020

ACS Omega

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Furosemide is a widely used diuretic for treating excessive fluid accumulation caused by disease conditions like heart failure and liver cirrhosis. Furosemide tablet formulation exhibits variable pharmacokinetics (PK) with bioavailability ranging from 10 to almost 100%. To explain the variable absorption, we integrated the physicochemical, in vitro dissolution, permeability, distribution, and the elimination parameters of furosemide in a physiologically-based pharmacokinetic (PBPK) model. Although the intravenous PBPK model reasonably described the observed in vivo PK data, the reported low passive permeability failed to capture the observed data after oral administration. To mechanistically justify this discrepancy, we hypothesized that transporter-mediated uptake contributes to the oral absorption of furosemide in conjunction with passive permeability. Our in vitro results confirmed that furosemide is a substrate of intestinal breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), and organic anion transporting polypeptide 2B1 (OATP2B1), but it is not a substrate of P-glycoprotein (P-gp) and MRP2. We then estimated the net transporter-mediated intestinal uptake and integrated it into the PBPK model under both fasting and fed conditions. Our in vitro data and PBPK model suggest that the absorption of furosemide is permeability-limited, and OATP2B1 and MRP4 are important for its permeability across intestinal membrane. Further, as furosemide has been proposed as a probe substrate of renal organic anion transporters (OATs) for assessing clinical drug–drug interactions (DDIs) during drug development, the confounding effects of intestinal transporters identified in this study on furosemide PK should be considered in the clinical transporter DDI studies.

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Section: Discussionsupporting

confidence: 56%

Contribution of Uptake and Efflux Transporters to Oral Pharmacokinetics of Furosemide

Chapa

Basit

et al. 2020

ACS Omega

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“…APOL1 expression is driven by inflammation, and its protein product has been found in endothelial and vascular smooth muscle cells within the kidney 16, 55. Among individuals with decompensated HF, different variants in the APOL1 gene have been associated with differential responsiveness to furosemide‐based diuretic regimens, and whether differences in response to medications may explain observed associations is not known 56. Perhaps the APOL1 risk variants increase risk for HF via endothelial dysfunction or abnormalities in cardiac remodeling.…”

Section: Discussionmentioning

confidence: 99%

“…16,55 Among individuals with decompensated HF, different variants in the APOL1 gene have been associated with differential responsiveness to furosemide-based diuretic regimens, and whether differences in response to medications may explain observed associations is not known. 56 Perhaps the APOL1 risk variants increase risk for HF via endothelial dysfunction or abnormalities in cardiac remodeling. Alternatively, the APOL1 risk variants may be associated with HF caused by effects on the kidney that are not sufficiently captured by traditional clinical markers or by causing defects in sodium handling.…”

Section: Discussionmentioning

confidence: 99%

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

Chen

Katz

Estrella

et al. 2017

JAHA

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Background APOL1 genetic variants confer an increased risk for kidney disease. Their associations with cardiovascular disease (CVD) are less certain. We aimed to compare the prevalence of subclinical CVD and incidence of atherosclerotic CVD and heart failure by APOL1 genotypes among self‐identified black participants of MESA (Multi‐Ethnic Study of Atherosclerosis).Methods and ResultsCross‐sectional associations of APOL1 genotypes (high‐risk=2 alleles; low‐risk=0 or 1 allele) with coronary artery calcification, carotid‐intimal media thickness, and left ventricular mass were evaluated using logistic and linear regression. Longitudinal associations of APOL1 genotypes with incident myocardial infarction, stroke, coronary heart disease, and congestive heart failure were examined using Cox regression. We adjusted for African ancestry, age, and sex. We also evaluated whether hypertension or kidney function markers explained the observed associations. Among 1746 participants with APOL1 genotyping (mean age 62 years, 55% women, mean cystatin C–based estimated glomerular filtration rate 89 mL/min per 1.73 m2, 12% with albuminuria), 12% had the high‐risk genotypes. We found no difference in prevalence or severity of coronary artery calcification, carotid‐intimal media thickness, or left ventricular mass by APOL1 genotypes. The APOL1 high‐risk group was 82% more likely to develop incident heart failure compared with the low‐risk group (95% confidence interval, 1.01–3.28). Adjusting for hypertension (hazard ratio, 1.80; 95% confidence interval, 1.00–3.24) but not markers of kidney function (hazard ratio, 1.86; 95% confidence interval, 1.03–3.35) slightly attenuated this association. The APOL1 high‐risk genotypes were not significantly associated with other clinical CVD outcomes.ConclusionsAmong blacks without baseline CVD, the APOL1 high‐risk variants may be associated with increased risk for incident heart failure but not subclinical CVD or incident clinical atherosclerotic CVD.

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“…The methods of the Heart Failure Network (HFN) genomics/pharmacogenomics sub-studies, including DNA extraction, genotyping and quality control have been previously reported. 18 The genotyping strategy included multiple commercial and custom platforms. Among the commercial platforms, we used Sequenom’s iPLEX ® ADME PGx Panel (Sequenom [now Agena Bioscience], San Diego, CA, USA) to genotype functional SNPs related to the absorption, distribution, metabolism and excretion (ADME).…”

Section: Methodsmentioning

confidence: 99%

CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction

et al. 2017

Self Cite

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Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic substudy of patients randomized to sildenafil (n = 85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.

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A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials

Cited by 12 publications

References 42 publications

Contribution of Uptake and Efflux Transporters to Oral Pharmacokinetics of Furosemide

Contribution of Uptake and Efflux Transporters to Oral Pharmacokinetics of Furosemide

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction

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