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Identification
Name Eplerenone
Accession Number DB00700 (APRD00707)
Type small molecule
Groups approved
Description

Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Epoxymexrenone
Salts Not Available
Brand names
Name Company
INSPRA
Brand mixtures Not Available
Categories
  • Antihypertensive Agents
  • Aldosterone Antagonists
CAS number 107724-20-9
Weight Average: 414.4914
Monoisotopic: 414.204238692
Chemical Formula C24H30O6
InChI Key InChIKey=JUKPWJGBANNWMW-VWBFHTRKSA-N
InChI
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
Plain Text
IUPAC Name
methyl (1'R,2R,2'S,9'R,10'R,11'S,15'S,17'R)-2',15'-dimethyl-5,5'-dioxo-18'-oxaspiro[oxolane-2,14'-pentacyclo[8.8.0.0^{1,17}.0^{2,7}.0^{11,15}]octadecan]-6'-ene-9'-carboxylate
SMILES
[H][C@@]12CC[C@@]3(CCC(=O)O3)[C@@]1(C)C[C@H]1O[C@@]11[C@@]2([H])[C@@H](CC2=CC(=O)CC[C@]12C)C(=O)OC
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For improvement of survival of stable patients with left ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of congestive heart failure after an acute myocardial infarction.
Pharmacodynamics Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors.
Mechanism of action Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms.
Absorption The absolute bioavailability of eplerenone is unknown.
Volume of distribution
  • 43 to 90 L
Protein binding 50%
Metabolism Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma.
Route of elimination Not Available
Half life 4-6 hours
Clearance
  • Apparent plasma cl=10 L/hr
Toxicity The most likely symptoms of human overdosage would be anticipated to be hypotension or hyperkalemia. However, no cases of human overdosage with eplerenone have been reported.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00135 Eplerenone Pathway SMP00135
Pharmacoeconomics
Manufacturers
  • Apotex inc
  • Sandoz inc
  • Gd searle llc
Packagers
Dosage forms
Form Route Strength
Tablet, film coated Oral
Prices
Unit description Cost Unit
Inspra 25 mg tablet 4.87 USD tablet
Inspra 50 mg tablet 4.87 USD tablet
Eplerenone 25 mg tablet 4.18 USD tablet
Eplerenone 50 mg tablet 4.18 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 6863902 2000-10-10 2020-10-10
United States 6410524 1999-11-05 2019-11-05
Properties
State solid
Experimental Properties
Property Value Source
water solubility Slightly soluble Not Available
logP 1.3 Not Available
Predicted Properties
Property Value Source
water solubility 9.03e-03 g/l ALOGPS
logP 1.67 ALOGPS
logP 2.33 ChemAxon
logS -4.7 ALOGPS
pKa (strongest acidic) 15.11 ChemAxon
pKa (strongest basic) -4.2 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 0 ChemAxon
polar surface area 82.2 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 106.68 ChemAxon
polarizability 43.79 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D01115 Link_out
KEGG Compound C12512 Link_out
ChEBI 31547 Link_out
ChEMBL 31547 Link_out
Therapeutic Targets Database DAP000085 Link_out
PharmGKB PA164749044 Link_out
IUPHAR 2876 Link_out
Guide to Pharmacology 2876 Link_out
RxList http://www.rxlist.com/cgi/generic/inspra.htm Link_out
Drugs.com http://www.drugs.com/cdi/eplerenone.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ins1681.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Eplerenone Link_out
ATC Codes
  • C03DA04
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (136 KB)
MSDS show (68.2 KB)
Interactions
Drug Interactions
Drug Interaction
Amiloride Increased risk of hyperkalemia. Monitor serum potassium levels during concomitant threapy.
Bicalutamide CYP3A4 Inhibitors like bicalutamide may increase the serum concentration of eplerenone. A lower starting dose of eplerenone (25 mg once daily) is recommended in patients with hypertension who are also taking drugs that are moderate inhibitors of CYP3A4.
Clarithromycin The macrolide, clarithromycin, may increase the effect and toxicity of eplerenone.
Conivaptan CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. The combination of eplerenone with any strong CYP3A4 inhibitor is contraindicated.
Erythromycin This CYP3A4 inhibitor increases the effect and toxicity of eplerenone
Fluconazole This CYP3A4 inhibitor increases the effect and toxicity of eplerenone
Itraconazole Itraconazole may increase the effect and toxicity of eplerenone.
Ketoconazole Ketoconazole, a CYP3A4 inhibitor, may increase the effect and toxicity of eplerenone.
Lithium Eplerenone increases serum levels of lithium
Nefazodone Nefazodone increases the effect and toxicity of eplerenone
Nelfinavir The protease inhibitor, nelfinavir, may increase the effect and toxicity of eplerenone.
Polystyrene sulfonate Risk of alkalosis in renal impairment
Potassium This association presents an increased risk of hyperkalemia
Ritonavir This protease inhibitor, ritonavir, may increase the effect and toxicity of eplerenone.
Saquinavir This CYP3A4 inhibitor increases the effect and toxicity of eplerenone
Spironolactone This association presents an increased risk of hyperkalemia
Telithromycin Telithromycin may reduce clearance of Eplerenone. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Eplerenone if Telithromycin is initiated, discontinued or dose changed.
Trandolapril Increased risk of hyperkalemia. Monitor serum potassium levels.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Triamterene This association presents an increased risk of hyperkalemia
Troleandomycin The macrolide, troleandomycin, may increase the effect and toxicity of eplerenone.
Verapamil This CYP3A4 inhibitor increases the effect and toxicity of eplerenone
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of eplerenone by decreasing its metabolism. Concomitant therapy is contraindicated.
Food Interactions Not Available
Targets

1. Mineralocorticoid receptor

Pharmacological action: yes
Actions: antagonist

Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels

Organism class: human
UniProt ID: P08235 Link_out
Gene: NR3C2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Moore TD, Nawarskas JJ, Anderson JR: Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure. Heart Dis. 2003 Sep-Oct;5(5):354-63. Pubmed
  2. Fraccarollo D, Galuppo P, Hildemann S, Christ M, Ertl G, Bauersachs J: Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. J Am Coll Cardiol. 2003 Nov 5;42(9):1666-73. Pubmed
  3. Rogerson FM, Yao Y, Smith BJ, Fuller PJ: Differences in the determinants of eplerenone, spironolactone and aldosterone binding to the mineralocorticoid receptor. Clin Exp Pharmacol Physiol. 2004 Oct;31(10):704-9. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A5

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 3A7

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

4. Cytochrome P450 11B2, mitochondrial

Actions: inhibitor

Preferentially catalyzes the conversion of 11- deoxycorticosterone to aldosterone via corticosterone and 18- hydroxycorticosterone

UniProt ID: P19099 Link_out
Gene: CYP11B2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19