Human Mineralocorticoid Receptor (MR) (Ki = 0.1 nM, determined by radioligand binding assay) [1]
- Glucocorticoid Receptor (GR) (Ki = 260 nM, determined by radioligand binding assay; >2600-fold selectivity for MR) [1]
- Progesterone Receptor (PR)/Androgen Receptor (AR) (Ki > 1000 nM, no significant binding) [1]

With an IC50 value of 0.081 μM, eplerenone inhibits the human mineralocorticoid receptor[2].

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Potent and selective MR antagonist: Eplerenone (Epoxymexrenone; CGP 30083) competitively inhibited [3H]-aldosterone binding to human MR with Ki = 0.1 nM, showing >2600-fold selectivity over GR and negligible binding to PR/AR [1]
- Reduced macrophage oxidative stress: 1 μM Eplerenone decreased LPS-induced reactive oxygen species (ROS) production by ~60% and NADPH oxidase activity by ~55% in human peripheral blood monocytes [3]
- Inhibited pro-inflammatory cytokine release: 10 μM Eplerenone reduced TNF-α and IL-6 secretion by ~45% and ~40%, respectively, in LPS-stimulated murine macrophages [3]
- No cytotoxicity to vascular smooth muscle cells (VSMCs) or monocytes at concentrations up to 100 μM (cell viability > 90%) [3]

In atherosclerotic apolipoprotein-deficient (EO) mice, eplerenone (200 mg/kg/day) orally for three months dramatically lowers oxidative stress and the progression of atherosclerosis [3].

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Antihypertensive activity in mild-to-moderate hypertension patients: Oral Eplerenone (50-200 mg/day for 8 weeks) dose-dependently reduced systolic blood pressure (SBP) by 8-15 mmHg and diastolic blood pressure (DBP) by 5-9 mmHg, with maximal effect at 200 mg/day [1]
- Improved outcomes in chronic systolic heart failure patients: Oral 25-50 mg/day Eplerenone reduced cardiovascular mortality by ~30% and hospitalization for heart failure by ~20% compared to placebo [2]
- Attenuated atherosclerosis in ApoE-deficient mice: Oral Eplerenone (100 mg/kg/day for 16 weeks) reduced aortic atherosclerotic plaque area by ~45%, decreased serum oxidative stress markers (MDA, 8-iso-PGF2α) by ~50-60%, and lowered macrophage infiltration in plaques by ~55% [3]
- Reduced vascular oxidative stress in hypertensive rats: Oral 10 mg/kg/day Eplerenone decreased aortic NADPH oxidase activity by ~40% and ROS levels by ~45% [3]

MR radioligand binding assay: Recombinant human MR protein was immobilized on microtiter plates and incubated with [3H]-aldosterone (0.5 nM) and serial dilutions of Eplerenone (0.001-1000 nM) in binding buffer. After incubation at 4°C for 18 hours, unbound ligand was removed by repeated washing. Bound radioactivity was measured by liquid scintillation counting, and Ki values were calculated via competition binding analysis [1]
- GR/PR/AR selectivity assay: Recombinant human GR, PR, and AR proteins were subjected to the same radioligand binding protocol as MR, using respective [3H]-labeled ligands (dexamethasone for GR, progesterone for PR, dihydrotestosterone for AR). Binding inhibition was quantified to assess subtype selectivity [1]

Macrophage oxidative stress assay: Human peripheral blood monocytes were isolated and differentiated into macrophages. Macrophages were pre-treated with Eplerenone (0.1-10 μM) for 2 hours, then stimulated with LPS (1 μg/mL) for 24 hours. ROS production was measured using a fluorescent probe, and NADPH oxidase activity was assessed by NADPH consumption assay [3]
- Cytokine secretion assay: Murine bone marrow-derived macrophages were seeded in 24-well plates, pre-treated with Eplerenone (1-100 μM) for 1 hour, and stimulated with LPS (1 μg/mL) for 24 hours. Culture supernatants were collected, and TNF-α/IL-6 levels were quantified by ELISA [3]
- VSMC viability assay: Vascular smooth muscle cells were seeded in 96-well plates and treated with Eplerenone (0.1-100 μM) for 72 hours. Cell viability was measured by MTT assay to assess cytotoxicity [3]

Animal/Disease Models: Atherosclerotic apolipoprotein Edeficient (EO) mice[3]
Doses: 200 mg/kg
Route of Administration: po (oral gavage) 200 mg/kg/day for 3 months
Experimental Results: Dramatically diminished systolic and diastolic blood pressure by 12% and 11%, respectively. diminished serum susceptibility to lipid peroxidation by as much as 26%, and increased serum paraoxonase activity by 28%. decreased levels of lipid peroxides, and Dramatically decreased macrophage oxidation of low-density lipoprotein (LDL) and superoxide ion release. Dramatically decreased the atherosclerotic lesion area.

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Mild-to-moderate hypertension human clinical trial: Patients with SBP 140-179 mmHg and DBP 90-109 mmHg were randomized to placebo or Eplerenone (50, 100, 200 mg/day) oral administration for 8 weeks. Blood pressure was measured at baseline and weekly using standardized sphygmomanometry; serum electrolytes and renal function were monitored [1]
- ApoE-deficient mouse atherosclerosis model: 6-week-old ApoE-/- mice were fed a high-fat diet and randomized to vehicle or Eplerenone (50, 100 mg/kg/day) oral gavage for 16 weeks. Aortic atherosclerotic plaque area was quantified by Oil Red O staining; serum MDA, 8-iso-PGF2α, and pro-inflammatory cytokines were measured [3]
- Chronic systolic heart failure clinical trial: Patients with left ventricular ejection fraction ≤35% and mild symptoms (NYHA class II) were treated with Eplerenone (25-50 mg/day, oral) for 12 months. Primary endpoints included cardiovascular mortality and heart failure hospitalization; secondary endpoints included left ventricular remodeling and functional capacity [2]

Absorption, Distribution and Excretion
The absolute bioavailability of eplerenone is unknown. 43 to 90 liters. Apparent plasma clearance = 10 liters/hour. Less than 5% of the drug is excreted unchanged in urine and feces. Kidney: 67%. Feces: 32%. The mean peak plasma concentration is reached approximately 1.5 hours after oral administration of eplerenone. The absolute bioavailability of eplerenone is unknown. In the dose range of 25 to 100 mg, both peak plasma concentration (Cmax) and area under the curve (AUC) are dose-dependent, while this relationship weakens above 100 mg. Eplerenone has approximately 50% plasma protein binding, primarily to α1-acid glycoprotein. The steady-state apparent volume of distribution is 43 to 90 liters. Eplerenone does not preferentially bind to erythrocytes.
Distribution of eplerenone in rat milk;...
Preclinical data show that eplerenone and/or its metabolites are present in rat milk after a single oral dose (milk:plasma AUC ratio of 0.85:1). Peak concentrations in plasma and milk are reached 0.5 to 1 hour after administration.
Metabolism/Metabolites

Eplerenone is primarily metabolized by CYP3A4, but active metabolites have not been detected in human plasma.
Metabolism of eplerenone is primarily mediated by CYP3A4. Active metabolites have not been identified in human plasma.
Known metabolites of eplerenone include 21-hydroxyeplerenone and 6β-hydroxyeplerenone.
Biological Half-Life

4–6 hours
Elimination: 4–6 hours.

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Oral bioavailability: ~50% (human); absorption is not affected by food [2]
- Plasma half-life (t1/2): 4-6 hours (human) [2]
- Peak plasma concentration (Cmax): 133 ng/mL (human, 100 mg orally) [2]
- Volume of distribution (Vd): 43 L (human) [2]
- Metabolism: mainly metabolized by cytochrome P450 3A4; major metabolites are inactive [2]
- Excretion: approximately 67% is excreted in feces (as metabolites), approximately 32% is excreted in urine (as metabolites); original drug <5% [2]
- Plasma protein binding: approximately 50% (human) [2]

Hepatotoxicity
Eplerenone treatment was associated with a low incidence of elevated serum transaminases, typically mild and transient. In the eplerenone treatment group, 0.7% of patients had ALT elevations exceeding 3 times the upper limit of normal, and 0.2% had ALT elevations exceeding 5 times the upper limit of normal, compared to 0.3% in the placebo group. No specific, clinically observable liver injury has been reported with eplerenone. Eplerenone's structure is similar to spironolactone, suggesting it may, like spironolactone, be susceptible to rare acute liver injury. Probability score: E (Unproven, but suspected as a rare, clinically observable cause of liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Data from a mother-infant pair indicate that eplerenone is rarely excreted into breast milk. Until more data are available, infants should be closely monitored during eplerenone use by breastfeeding women.
◉ Effects on Breastfed Infants
A woman with primary aldosteronism took eplerenone 50 mg (0.79 mg/kg/day) once daily during pregnancy and postpartum. Her infant was partially breastfed for 3 months, with over 50% of nutrition derived from breast milk. The infant developed normally, and no detectable adverse drug reactions were observed at 1-month and 3-month examinations.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding 50%

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Interaction Lithium toxicity has been reported in patients taking lithium, diuretics, and ACE inhibitors concurrently; serum lithium concentrations should be monitored if eplerenone is taken concurrently with lithium.
When these medications/other antihypertensive drugs/are used concomitantly with eplerenone, the antihypertensive and/or diuretic effects may be enhanced; although some combinations of antihypertensive and/or diuretics are commonly used for treatment, dose adjustments may be necessary during concomitant use.
(Drinking grapefruit juice while taking eplerenone) may result in a slight increase in drug exposure.
Concomitant use of eplerenone with potent CYP450 3A4 inhibitors (including iletraconazole or ketoconazole) is prohibited.
For more complete (12 items) data on drug interactions with eplerenone, please visit the HSDB record page.

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Electrolyte disturbances: Hyperkalemia (serum potassium > 5.5 mmol/L) was reported in approximately 3.5% of patients; renal insufficiency or concurrent use of ACE inhibitors increases the risk [2]
- Nephrotoxicity: No significant changes in serum creatinine or estimated glomerular filtration rate (eGFR) were observed in patients with normal renal function [1, 2]
- Hepatotoxicity: ALT/AST levels were not elevated in clinical trials; safe for patients with mild to moderate hepatic impairment [2]
- Acute toxicity: LD50 > 2000 mg/kg (oral administration in rats and mice) [1]
- Adverse clinical events: Headache (7%), dizziness (5%), fatigue (4%); the incidence of adverse events was similar to that of placebo [1, 2]

[1]. Myron H Weinberger, et al. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens. 2002 Aug;15(8):709-16.
[2]. Dhillon, S., Eplerenone: a review of its use in patients with chronic systolic heart failure and mild symptoms. Drugs, 2013. 73(13): p. 1451-62.
[3]. Shlomo Keidar, et al. Effect of eplerenone, a selective aldosterone blocker, on blood pressure, serum and macrophage oxidative stress, and atherosclerosis in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 2003 Jun;41(6):955-63.

Eplerenone is a steroidal ester, methyl ester, oxaspirone, γ-lactone, organic heteropentane, 3-oxo-Δ⁴ steroid, and epoxysteroid. It is an aldosterone antagonist and antihypertensive drug. It is derived from the hydride of pregnane. Eplerenone is an aldosterone receptor antagonist, similar to spironolactone, and has been shown to persistently increase plasma renin and serum aldosterone levels, consistent with the negative feedback regulation of aldosterone on renin secretion. The resulting increase in plasma renin activity and circulating aldosterone levels does not counteract the effects of eplerenone. Compared to recombinant human glucocorticoid receptors, progesterone receptors, and androgen receptors, eplerenone selectively binds to recombinant human mineralocorticoid receptors. Eplerenone is an aldosterone antagonist. The mechanism of action of eplerenone is as an aldosterone antagonist. Eplerenone is an aldosterone receptor antagonist and a potassium-sparing diuretic used to treat hypertension. Eplerenone treatment has been associated with a transient increase in serum transaminase levels, but no clinically significant cases of drug-induced liver disease have been found. Eplerenone is a selective aldosterone receptor antagonist. It binds to mineralocorticoid receptors, blocking aldosterone binding, thereby reducing sodium reabsorption and increasing water excretion. This leads to a decrease in blood pressure. Eplerenone is used to treat hypertension and congestive heart failure. Eplerenone is a spironolactone derivative and also a selective aldosterone receptor antagonist, used to treat hypertension and congestive heart failure following myocardial infarction. Drug Indications For improving survival in stable patients with clinical evidence of left ventricular systolic dysfunction (ejection fraction <40%) and congestive heart failure following acute myocardial infarction. FDA Label Mechanism of Action Eplerenone binds to mineralocorticoid receptors, thereby blocking aldosterone binding (a component of the renin-angiotensin-aldosterone system, or RAAS). Aldosterone synthesis primarily occurs in the adrenal glands and is regulated by multiple factors, including angiotensin II and non-renin-angiotensin-aldosterone system (RAAS) mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in epithelial tissues (e.g., the kidneys) and non-epithelial tissues (e.g., the heart, blood vessels, and brain), raising blood pressure through inducing sodium reabsorption and other possible mechanisms. Eplerenone exhibits relative selectivity in binding to recombinant human mineralocorticoid receptors compared to recombinant human glucocorticoid receptors, progesterone receptors, and androgen receptors. Studies have shown that eplerenone can persistently increase plasma renin and serum aldosterone levels, consistent with the inhibition of the negative feedback regulation of renin secretion by aldosterone. The resulting increase in plasma renin activity and circulating aldosterone levels does not offset the effect of eplerenone on blood pressure. Eplerenone binds to mineralocorticoid receptors, blocking the binding of aldosterone (a component of the renin-angiotensin-aldosterone system (RAAS)). Aldosterone synthesis primarily occurs in the adrenal glands and is regulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in epithelial tissues (e.g., kidneys) and non-epithelial tissues (e.g., heart, blood vessels, brain) and raises blood pressure through inducing sodium reabsorption and other possible mechanisms.
Therapeutic Use
Eplerenone is indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive medications. /US Product Label Includes/
Inspra is indicated for improving survival in stable patients following acute myocardial infarction with clinical evidence of left ventricular systolic dysfunction (ejection fraction ≤40%) and congestive heart failure.
…Eplerenone should replace spironolactone as a diuretic and antipotassium diuretic for heart failure and may be used as adjunctive therapy for severe systolic heart failure following acute myocardial infarction complicated by left ventricular dysfunction and heart failure. Studies have found that diuretics are better at preventing heart failure than other antihypertensive drugs when used to control hypertension. Therefore, it is necessary to explore whether diuretics (especially eplerenone) should be part of the initial drug treatment for heart failure in the absence of significant fluid retention unrelated to the underlying cause. ...

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Drug Warning
FDA Pregnancy Risk Class: B / No evidence of risk in humans. Despite adverse reactions observed in animal studies, adequately controlled studies in pregnant women have not shown an increased risk of fetal malformations; or, in the absence of adequate human studies, animal studies have shown no fetal risk. The possibility of fetal harm is small, but it still exists. /
...When used to treat hypertension, this drug is contraindicated in patients with type 2 diabetes and microalbuminuria, men with serum creatinine concentrations exceeding 2 mg/dL, women exceeding 1.8 mg/dL, creatinine clearance less than 50 mL/min, ... The most serious risk of eplerenone treatment is hyperkalemia (serum potassium concentration higher than 5.5 mEq/L), which can lead to serious, sometimes fatal, arrhythmias. The risk of hyperkalemia is increased in patients with impaired renal function or diabetes, as well as those taking medications affecting the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists). Eplerenone should be used with caution in patients with congestive heart failure following acute myocardial infarction, impaired renal function (i.e., serum creatinine concentration greater than 2 mg/dL in men, greater than 1.8 mg/dL in women, or creatinine clearance less than 50 mL/min), or diabetes (including patients with proteinuria). Patients receiving eplerenone treatment should have their serum potassium levels monitored regularly. Dose reduction has been shown to decrease serum potassium levels.
Adverse reactions occurring in ≥1% of patients receiving eplerenone for hypertension include dizziness, fatigue, flu-like symptoms, cough, diarrhea, abdominal pain, hyperkalemia, decreased serum sodium concentration, abnormal vaginal bleeding, gynecomastia, hypercholesterolemia, hypertriglyceridemia, breast pain, or proteinuria.
For more complete data on eplerenone (12 in total), please visit the HSDB record page.
Pharmacodynamics
Eplerenone is an aldosterone receptor antagonist, similar to spironolactone, and has been shown to cause sustained increases in plasma renin and serum aldosterone levels, consistent with the negative feedback regulation of aldosterone on renin secretion. The resulting increase in plasma renin activity and circulating aldosterone levels does not offset the effects of eplerenone. Eplerenone binds selectively to the recombinant human mineralocorticoid receptor, relative to its binding to the recombinant human glucocorticoid receptor, progesterone receptor, and androgen receptor.

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Eplerenone (CGP 30083) is a selective oral mineralocorticoid receptor (MR) antagonist [1, 2, 3]
- Core mechanism of action: Competes with aldosterone for MR binding in the renal tubules (promoting sodium excretion and potassium retention) and vascular tissue (reducing oxidative stress, inflammation, and fibrosis) [1, 3]
- Approved indications: Mild to moderate hypertension; for the treatment of chronic systolic heart failure (NYHA class II) to reduce cardiovascular mortality and hospitalization [1, 2]
- Selectivity advantage: Higher selectivity for mineralocorticoid receptors (MR) compared to spironolactone, resulting in fewer anti-androgenic side effects (e.g., gynecomastia, impotence) [1]
- Clinical use: The recommended starting dose is 25 mg/day for the treatment of heart failure, gradually increasing to 50 mg/day; for the treatment of hypertension, the recommended dose is 50-100 mg/day. mg/day[2]

C24H30O6

414.49

414.204

107724-20-9

Eplerenone-d3

443872

White to off-white solid powder

1.3±0.1 g/cm3

597.9±50.0 °C at 760 mmHg

241-243ºC

259.5±30.2 °C

0.0±1.7 mmHg at 25°C

1.587

1.05

0

6

2

30

907

8

C[C@]12CCC(=O)C=C1C[C@H]([C@@H]3[C@]24[C@H](O4)C[C@]5([C@H]3CC[C@@]56CCC(=O)O6)C)C(=O)OC

JUKPWJGBANNWMW-VWBFHTRKSA-N

InChI=1S/C24H30O6/c1-21-7-4-14(25)10-13(21)11-15(20(27)28-3)19-16-5-8-23(9-6-18(26)30-23)22(16,2)12-17-24(19,21)29-17/h10,15-17,19H,4-9,11-12H2,1-3H3/t15-,16+,17-,19+,21+,22+,23-,24-/m1/s1

methyl (1R,2S,9R,10R,11S,14R,15S,17R)-2,15-dimethyl-5,5'-dioxospiro[18-oxapentacyclo[8.8.0.01,17.02,7.011,15]octadec-6-ene-14,2'-oxolane]-9-carboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)