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Identification
NameEplerenone
Accession NumberDB00700  (APRD00707)
Typesmall molecule
Groupsapproved
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
Synonyms
SynonymLanguageCode
EpoxymexrenoneNot AvailableNot Available
InspraNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
INSPRANot Available
Brand mixturesNot Available
Categories
CAS number107724-20-9
WeightAverage: 414.4914
Monoisotopic: 414.204238692
Chemical FormulaC24H30O6
InChI KeyJUKPWJGBANNWMW-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
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassSteroids and Steroid Derivatives
SubclassOther Steroids and Derivatives
Direct parentOther Steroids and Derivatives
Alternative parentsSesquiterpenes; Oxepanes; Dicarboxylic Acids and Derivatives; Oxolanes; Tetrahydrofurans; Lactones; Ketones; Carboxylic Acid Esters; Ethers; Enolates; Polyamines; Epoxides
Substituentssesquiterpene backbone; oxepane; dicarboxylic acid derivative; gamma butyrolactone; oxolane; tetrahydrofuran; ketone; lactone; carboxylic acid ester; oxirane; ether; enolate; polyamine; carboxylic acid derivative; carbonyl group
Classification descriptionThis compound belongs to the other steroids and derivatives.
Pharmacology
IndicationFor 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.
PharmacodynamicsEplerenone, 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 actionEplerenone 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.
AbsorptionThe absolute bioavailability of eplerenone is unknown.
Volume of distribution
  • 43 to 90 L
Protein binding50%
Metabolism

Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma.

Route of eliminationNot Available
Half life4-6 hours
Clearance
  • Apparent plasma cl=10 L/hr
ToxicityThe 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
PathwayCategorySMPDB ID
Eplerenone Action PathwayDrug actionSMP00135
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9839
Blood Brain Barrier + 0.8556
Caco-2 permeable + 0.5076
P-glycoprotein substrate Substrate 0.7017
P-glycoprotein inhibitor I Inhibitor 0.8166
P-glycoprotein inhibitor II Inhibitor 0.8066
Renal organic cation transporter Non-inhibitor 0.7209
CYP450 2C9 substrate Non-substrate 0.8229
CYP450 2D6 substrate Non-substrate 0.9117
CYP450 3A4 substrate Substrate 0.7407
CYP450 1A2 substrate Non-inhibitor 0.6978
CYP450 2C9 substrate Non-inhibitor 0.7982
CYP450 2D6 substrate Non-inhibitor 0.931
CYP450 2C19 substrate Non-inhibitor 0.839
CYP450 3A4 substrate Non-inhibitor 0.8368
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8902
Ames test Non AMES toxic 0.7496
Carcinogenicity Non-carcinogens 0.9441
Biodegradation Not ready biodegradable 0.9891
Rat acute toxicity 2.4761 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9453
hERG inhibition (predictor II) Non-inhibitor 0.7742
Pharmacoeconomics
Manufacturers
  • Apotex inc
  • Sandoz inc
  • Gd searle llc
Packagers
Dosage forms
FormRouteStrength
Tablet, film coatedOral
Prices
Unit descriptionCostUnit
Inspra 25 mg tablet4.87USDtablet
Inspra 50 mg tablet4.87USDtablet
Eplerenone 25 mg tablet4.18USDtablet
Eplerenone 50 mg tablet4.18USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States68639022000-10-102020-10-10
United States64105241999-11-052019-11-05
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilitySlightly solubleNot Available
logP1.3Not Available
Predicted Properties
PropertyValueSource
water solubility9.03e-03 g/lALOGPS
logP1.67ALOGPS
logP2.33ChemAxon
logS-4.7ALOGPS
pKa (strongest acidic)15.11ChemAxon
pKa (strongest basic)-4.2ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count0ChemAxon
polar surface area82.2ChemAxon
rotatable bond count2ChemAxon
refractivity106.68ChemAxon
polarizability43.79ChemAxon
number of rings6ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Bhaskar Reddy Guntoori, Svetoslav S. Bratovanov, Mohamed Ibrahim Zaki, Elena Bejan, Stephen E. Horne, “Process for the preparation and purification of eplerenone.” U.S. Patent US20080234478, issued September 25, 2008.

US20080234478
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD01115
KEGG CompoundC12512
ChEBI31547
ChEMBLCHEMBL1095097
Therapeutic Targets DatabaseDAP000085
PharmGKBPA164749044
IUPHAR2876
Guide to Pharmacology2876
RxListhttp://www.rxlist.com/cgi/generic/inspra.htm
Drugs.comhttp://www.drugs.com/cdi/eplerenone.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ins1681.shtml
WikipediaEplerenone
ATC CodesC03DA04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(136 KB)
MSDSshow(68.2 KB)
Interactions
Drug Interactions
Drug
AmilorideIncreased risk of hyperkalemia. Monitor serum potassium levels during concomitant threapy.
BicalutamideCYP3A4 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.
ClarithromycinThe macrolide, clarithromycin, may increase the effect and toxicity of eplerenone.
ConivaptanCYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. The combination of eplerenone with any strong CYP3A4 inhibitor is contraindicated.
ErythromycinThis CYP3A4 inhibitor increases the effect and toxicity of eplerenone
FluconazoleThis CYP3A4 inhibitor increases the effect and toxicity of eplerenone
ItraconazoleItraconazole may increase the effect and toxicity of eplerenone.
KetoconazoleKetoconazole, a CYP3A4 inhibitor, may increase the effect and toxicity of eplerenone.
LithiumEplerenone increases serum levels of lithium
NefazodoneNefazodone increases the effect and toxicity of eplerenone
NelfinavirThe protease inhibitor, nelfinavir, may increase the effect and toxicity of eplerenone.
Polystyrene sulfonateRisk of alkalosis in renal impairment
PotassiumThis association presents an increased risk of hyperkalemia
RitonavirThis protease inhibitor, ritonavir, may increase the effect and toxicity of eplerenone.
SaquinavirThis CYP3A4 inhibitor increases the effect and toxicity of eplerenone
SpironolactoneThis association presents an increased risk of hyperkalemia
TelithromycinTelithromycin 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.
TrandolaprilIncreased risk of hyperkalemia. Monitor serum potassium levels.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
TriamtereneThis association presents an increased risk of hyperkalemia
TroleandomycinThe macrolide, troleandomycin, may increase the effect and toxicity of eplerenone.
VerapamilThis CYP3A4 inhibitor increases the effect and toxicity of eplerenone
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of eplerenone by decreasing its metabolism. Concomitant therapy is contraindicated.
Food InteractionsNot Available

Targets

1. Mineralocorticoid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Mineralocorticoid receptor P08235 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 11B2, mitochondrial P19099 Details

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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11