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Identification
NameSpironolactone
Accession NumberDB00421  (APRD01234)
Typesmall molecule
Groupsapproved
Description

A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. (From Martindale, The Extra Pharmacopoeia, 30th ed, p827)

Structure
Thumb
Synonyms
SynonymLanguageCode
EspironolactonaSpanishINN
SpironolactoneNot AvailableINN, BAN, JAN
SpironolactonumLatinINN
SpironolattoneNot AvailableDCIT
SaltsNot Available
Brand names
NameCompany
AldactoneNot Available
OsyrolNot Available
SpiresisNot Available
SpireticNot Available
SpiroctanNot Available
UractoneNot Available
VerospironNot Available
XenalonNot Available
Brand mixtures
Brand NameIngredients
Aldactazide 2525 mg Hydrochlorothiazide + 25 mg Spironolactone
Aldactazide 5050 mg Hydrochlorothiazide + 50 mg Spironolactone
Apo-Spirozide TabHydrochlorothiazide + Spironolactone
Novo-Spirozine Tab 25mgHydrochlorothiazide + Spironolactone
Novo-Spirozine-50 TabHydrochlorothiazide + Spironolactone
Categories
CAS number52-01-7
WeightAverage: 416.573
Monoisotopic: 416.202130202
Chemical FormulaC24H32O4S
InChI KeyInChIKey=LXMSZDCAJNLERA-ZHYRCANASA-N
InChI
InChI=1S/C24H32O4S/c1-14(25)29-19-13-15-12-16(26)4-8-22(15,2)17-5-9-23(3)18(21(17)19)6-10-24(23)11-7-20(27)28-24/h12,17-19,21H,4-11,13H2,1-3H3/t17-,18-,19+,21+,22-,23-,24+/m0/s1
IUPAC Name
(1'S,2R,2'R,9'R,10'R,11'S,15'S)-9'-(acetylsulfanyl)-2',15'-dimethylspiro[oxolane-2,14'-tetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadecan]-6'-ene-5,5'-dione
SMILES
[H][C@@]12CC[C@@]3(CCC(=O)O3)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])[C@@]([H])(CC2=CC(=O)CC[C@]12C)SC(C)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassSteroids and Steroid Derivatives
SubclassSteroid Lactones
Direct parentSteroid Lactones
Alternative parentsAndrogens and Derivatives; Ketosteroids; Thioesters; Tetrahydrofurans; Oxolanes; Lactones; Carboxylic Acid Esters; Ketones; Thiocarboxylic Acid Esters; Enolates; Polyamines
Substituentsandrogen-skeleton; 3-keto-steroid; gamma butyrolactone; tetrahydrofuran; carboxylic-thioester; oxolane; carboxylic acid ester; thiocarboxylic acid ester; lactone; ketone; enolate; polyamine; thiocarboxylic acid derivative; carboxylic acid derivative; carbonyl group
Classification descriptionThis compound belongs to the steroid lactones. These are sterol lipids containing a lactone moiety linked to the steroid skeleton.
Pharmacology
IndicationUsed primarily to treat low-renin hypertension, hypokalemia, and Conn's syndrome.
PharmacodynamicsSpironolactone is a synthetic 17-lactone steroid which is a renal competitive aldosterone antagonist in a class of pharmaceuticals called potassium-sparing diuretics. On its own, spironolactone is only a weak diuretic, but it can be combined with other diuretics. Due to its anti-androgen effect, it can also be used to treat hirsutism, and is a common component in hormone therapy for male-to-female transgendered people. Spironolactone inhibits the effect of aldosterone by competing for intracellular aldosterone receptor in the distal tubule cells. This increases the secretion of water and sodium, while decreasing the excretion of potassium. Spironolactone has a fairly slow onset of action, taking several days to develop and similarly the effect diminishes slowly.
Mechanism of actionSpironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule. Aldosterone interacts with a cytoplasmic mineralocorticoid receptor to enhance the expression of the Na+, K+-ATPase and the Na+ channel involved in a Na+ K+ transport in the distal tubule . Spironolactone bind to this mineralcorticoid receptor, blocking the actions of aldosterone on gene expression. Aldosterone is a hormone; its primary function is to retain sodium and excrete potassium in the kidneys.
AbsorptionFairly rapidly absorbed from the gastrointestinal tract. Food increases the bioavailability of unmetabolized spironolactone by almost 100%.
Volume of distributionNot Available
Protein bindingSpironolactone and its metabolites are more than 90% bound to plasma proteins.
Metabolism

Rapidly and extensively metabolized. The metabolic pathway of spironolactone is complex and can be divided into two main routes: those in which the sulfur moiety is retained and those in which the sulfur moiety is removed by dethioacetylation. Spironolactone is transformed to a reactive metabolite that can inactivate adrenal and testicular cytochrome P450 enzymes. It also has anti-androgenic activity.

Route of eliminationThe metabolites are excreted primarily in the urine and secondarily in bile.
Half life10 minutes
ClearanceNot Available
ToxicityThe oral LD50 of spironolactone is greater than 1,000 mg/kg in mice, rats, and rabbits. Acute overdosage of spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Spironolactone Action PathwayDrug actionSMP00134
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9912
Blood Brain Barrier + 0.932
Caco-2 permeable + 0.5432
P-glycoprotein substrate Substrate 0.5691
P-glycoprotein inhibitor I Inhibitor 0.6807
P-glycoprotein inhibitor II Inhibitor 0.8388
Renal organic cation transporter Non-inhibitor 0.727
CYP450 2C9 substrate Non-substrate 0.7897
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.6638
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9276
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8681
Ames test Non AMES toxic 0.9158
Carcinogenicity Non-carcinogens 0.9288
Biodegradation Not ready biodegradable 0.9696
Rat acute toxicity 2.0150 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9427
hERG inhibition (predictor II) Non-inhibitor 0.7002
Pharmacoeconomics
Manufacturers
  • Gd searle llc
  • Actavis elizabeth llc
  • Amneal pharmaceuticals
  • Ascot hosp pharmaceuticals inc div travenol laboratories inc
  • Ivax pharmaceuticals inc
  • Lederle laboratories div american cyanamid co
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Purepac pharmaceutical co
  • Sandoz inc
  • Superpharm corp
  • Upsher smith laboratories inc
  • Vangard laboratories inc div midway medical co
  • Vintage pharmaceuticals llc
  • Warner chilcott div warner lambert co
  • Watson laboratories inc
Packagers
Dosage forms
FormRouteStrength
Tablet, film coatedOral100 mg
Tablet, film coatedOral25 mg
Tablet, film coatedOral50 mg
Prices
Unit descriptionCostUnit
Spironolactone powder12.56USDg
Aldactone 100 mg tablet2.14USDtablet
Aldactazide 50-50 mg tablet2.02USDtablet
Aldactazide 50-50 tablet1.92USDtablet
Aldactone 50 mg tablet1.84USDtablet
Spironolactone 100 mg tablet1.45USDtablet
Aldactazide 25-25 mg tablet1.26USDtablet
Aldactazide 25-25 tablet1.04USDtablet
Spironolactone 50 mg tablet0.83USDtablet
Aldactone 25 mg tablet0.8USDtablet
Spironolactone-HCTZ 25-25 mg tablet0.57USDtablet
Spironolactone 25 mg tablet0.5USDtablet
Novo-Spiroton 100 mg Tablet0.25USDtablet
Novo-Spiroton 25 mg Tablet0.11USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point134.5 °CPhysProp
water solubility22 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP2.78HANSCH,C ET AL. (1995)
logS-4.28ADME Research, USCD
Predicted Properties
PropertyValueSource
water solubility1.98e-03 g/lALOGPS
logP3.1ALOGPS
logP3.64ChemAxon
logS-5.3ALOGPS
pKa (strongest acidic)18.01ChemAxon
pKa (strongest basic)-4.9ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count0ChemAxon
polar surface area60.44ChemAxon
rotatable bond count2ChemAxon
refractivity113.5ChemAxon
polarizability46.03ChemAxon
number of rings5ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Giuseppe Bernini, “Process for preparing micronized spironolactone.” U.S. Patent US4332721, issued July, 1975.

US4332721
General Reference
  1. Berardesca E, Gabba P, Ucci G, Borroni G, Rabbiosi G: Topical spironolactone inhibits dihydrotestosterone receptors in human sebaceous glands: an autoradiographic study in subjects with acne vulgaris. Int J Tissue React. 1988;10(2):115-9. Pubmed
  2. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep 2;341(10):709-17. Pubmed
  3. Wandelt-Freerksen E: [Aldactone in the treatment of sarcoidosis of the lungs (author’s transl)] Z Erkr Atmungsorgane. 1977 Jul;149(1):156-9. Pubmed
External Links
ResourceLink
KEGG DrugD00443
KEGG CompoundC07310
PubChem Compound5833
PubChem Substance46508525
ChemSpider5628
BindingDB50228080
ChEBI9241
ChEMBLCHEMBL1393
Therapeutic Targets DatabaseDAP000297
PharmGKBPA451483
IUPHAR2875
Guide to Pharmacology2875
HETSNL
Drug Product Database613223
RxListhttp://www.rxlist.com/cgi/generic/spiron.htm
Drugs.comhttp://www.drugs.com/spironolactone.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ald1010.shtml
WikipediaSpironolactone
ATC CodesC03DA01
AHFS Codes
  • 24:32.20
PDB EntriesNot Available
FDA labelshow(395 KB)
MSDSshow(72.6 KB)
Interactions
Drug Interactions
Drug
BenazeprilIncreased risk of hyperkalemia
CandesartanIncreased risk of hyperkalemia
CaptoprilIncreased risk of hyperkalemia
CholestyramineIncreased risk of acidosis and hyperkalemia
CilazaprilIncreased risk of hyperkalemia
DigoxinIncreased digoxin levels and decreased effect in presence of spironolactone
EnalaprilIncreased risk of hyperkalemia
EplerenoneThis association presents an increased risk of hyperkalemia
EprosartanIncreased risk of hyperkalemia
FosinoprilIncreased risk of hyperkalemia
IrbesartanIncreased risk of hyperkalemia
LisinoprilIncreased risk of hyperkalemia
LosartanIncreased risk of hyperkalemia
MitotaneSpironolactone antagonizes the effect of mitotane
PerindoprilIncreased risk of hyperkalemia
Polystyrene sulfonateRisk of alkalosis in renal impairment
PotassiumIncreased risk of hyperkalemia
QuinaprilIncreased risk of hyperkalemia
RamiprilIncreased risk of hyperkalemia
TelmisartanTelmisartan may increase the hyperkalemic effect of Spironolactone. Monitor for increased serum potassium concentrations during concomitant therapy.
TobramycinIncreased risk of nephrotoxicity
TrandolaprilIncreased risk of hyperkalemia. Monitor serum potassium levels.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food Interactions
  • Avoid alcohol.
  • Food increases the bioavailability of spironolactone by almost 100%.
  • Spironolactone may decrease the excretion of potassium. Salt substitutes containing potassium increase the risk of hyperkalemia.

1. Mineralocorticoid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Mineralocorticoid receptor P08235 Details

References:

  1. Sitruk-Ware R: Progestogens in hormonal replacement therapy: new molecules, risks, and benefits. Menopause. 2002 Jan-Feb;9(1):6-15. Pubmed
  2. Rogerson FM, Yao YZ, Smith BJ, Dimopoulos N, Fuller PJ: Determinants of spironolactone binding specificity in the mineralocorticoid receptor. J Mol Endocrinol. 2003 Dec;31(3):573-82. Pubmed
  3. Gertner RA, Klein JD, Bailey JL, Kim DU, Luo XH, Bagnasco SM, Sands JM: Aldosterone decreases UT-A1 urea transporter expression via the mineralocorticoid receptor. J Am Soc Nephrol. 2004 Mar;15(3):558-65. Pubmed
  4. Frishman WH, Stier CT Jr: Aldosterone and aldosterone antagonism in systemic hypertension. Curr Hypertens Rep. 2004 Jun;6(3):195-200. Pubmed
  5. 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
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Sica DA: Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. Heart Fail Rev. 2005 Jan;10(1):23-9. Pubmed
  8. Rossi G, Boscaro M, Ronconi V, Funder JW: Aldosterone as a cardiovascular risk factor. Trends Endocrinol Metab. 2005 Apr;16(3):104-7. Pubmed

2. Androgen receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Androgen receptor P10275 Details

References:

  1. Ye P, Yamashita T, Pollock DM, Sasano H, Rainey WE: Contrasting effects of eplerenone and spironolactone on adrenal cell steroidogenesis. Horm Metab Res. 2009 Jan;41(1):35-9. Epub 2008 Sep 25. Pubmed

1. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Walsky RL, Gaman EA, Obach RS: Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78. Pubmed
  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 11B1, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 11B1, mitochondrial P15538 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

1. Canalicular multispecific organic anion transporter 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Canalicular multispecific organic anion transporter 1 Q92887 Details

References:

  1. Johnson DR, Klaassen CD: Regulation of rat multidrug resistance protein 2 by classes of prototypical microsomal enzyme inducers that activate distinct transcription pathways. Toxicol Sci. 2002 Jun;67(2):182-9. Pubmed

2. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Wang E, Lew K, Barecki M, Casciano CN, Clement RP, Johnson WW: Quantitative distinctions of active site molecular recognition by P-glycoprotein and cytochrome P450 3A4. Chem Res Toxicol. 2001 Dec;14(12):1596-603. Pubmed

3. Solute carrier organic anion transporter family member 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1A2 P46721 Details

References:

  1. Kanai N, Lu R, Bao Y, Wolkoff AW, Schuster VL: Transient expression of oatp organic anion transporter in mammalian cells: identification of candidate substrates. Am J Physiol. 1996 Feb;270(2 Pt 2):F319-25. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:10