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Identification
Name Spironolactone
Accession Number DB00421 (APRD01234)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Brand names
  • Abbolactone
  • Acelat
  • Aldace
  • Aldactazide
  • Aldactide
  • Aldactone
  • Aldactone A
  • Alderon
  • Aldopur
  • Almatol
  • Altex
  • Aquareduct
  • Deverol
  • Diatensec
  • Dira
  • Duraspiron
  • Espironolactona [INN-Spanish]
  • Euteberol
  • Lacalmin
  • Lacdene
  • Laractone
  • Melarcon
  • Nefurofan
  • Osyrol
  • Sagisal
  • Sincomen
  • SNL
  • Spiresis
  • Spiretic
  • Spiridon
  • Spiro-Tablinen
  • Spiroctan
  • Spiroctanie
  • Spiroderm
  • Spirolactone
  • Spirolakton
  • Spirolang
  • Spirolone
  • Spirone
  • Spironocompren
  • Spironolactone [BAN:INN:JAN]
  • Spironolactone A
  • Spironolactonum [INN-Latin]
  • Spironolattone [DCIT]
  • Sprioderm
  • Supra-puren
  • Suracton
  • Uractone
  • Urusonin
  • Verospiron
  • Verospirone
  • Verospirone Opianin
  • Xenalon
Brand name mixtures
  • Aldactazide 25 (25 mg Hydrochlorothiazide + 25 mg Spironolactone)
  • Aldactazide 50 (50 mg Hydrochlorothiazide + 50 mg Spironolactone)
  • Apo-Spirozide Tab (Hydrochlorothiazide + Spironolactone)
  • Novo-Spirozine Tab 25mg (Hydrochlorothiazide + Spironolactone)
  • Novo-Spirozine-50 Tab (Hydrochlorothiazide + Spironolactone)
Categories
  • Diuretics
  • Aldosterone Antagonists
CAS number 52-01-7
Weight Average: 416.573
Monoisotopic: 416.202130202
Chemical Formula C24H32O4S
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Steroids and Steroid Derivatives
Substructures
  • Steroids and Steroid Derivatives
  • Carboxylic Acids and Derivatives
  • Alkanes and Alkenes
  • Acetates
  • Lactones
  • Ethers
  • Esters
  • Heterocyclic compounds
  • Furans
  • Cyclohexenes and Derivatives
  • Ketones
Pharmacology
Indication Used primarily to treat low-renin hypertension, hypokalemia, and Conn's syndrome.
Pharmacodynamics Spironolactone 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 action Spironolactone 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.
Absorption Fairly rapidly absorbed from the gastrointestinal tract. Food increases the bioavailability of unmetabolized spironolactone by almost 100%.
Volume of distribution Not Available
Protein binding Spironolactone 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 elimination The metabolites are excreted primarily in the urine and secondarily in bile.
Half life 10 minutes
Clearance Not Available
Toxicity The 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
Pathway Name SMPDB ID
Smp00134 Spironolactone Pathway SMP00134
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
Form Route Strength
Tablet, film coated Oral 100 mg
Tablet, film coated Oral 25 mg
Tablet, film coated Oral 50 mg
Prices
Unit description Cost Unit
Spironolactone powder 12.56 USD g
Aldactone 100 mg tablet 2.14 USD tablet
Aldactazide 50-50 mg tablet 2.02 USD tablet
Aldactazide 50-50 tablet 1.92 USD tablet
Aldactone 50 mg tablet 1.84 USD tablet
Spironolactone 100 mg tablet 1.45 USD tablet
Aldactazide 25-25 mg tablet 1.26 USD tablet
Aldactazide 25-25 tablet 1.04 USD tablet
Spironolactone 50 mg tablet 0.83 USD tablet
Aldactone 25 mg tablet 0.8 USD tablet
Spironolactone-HCTZ 25-25 mg tablet 0.57 USD tablet
Spironolactone 25 mg tablet 0.5 USD tablet
Novo-Spiroton 100 mg Tablet 0.25 USD tablet
Novo-Spiroton 25 mg Tablet 0.11 USD tablet
Patents Not Available
Properties
State solid
Melting point 134.5 oC
Experimental Properties
Property Value Source
water solubility Practically insoluble (22 mg/L) PhysProp
logP 3.4 PhysProp
logS -4.28 [ADME Research, USCD] PhysProp
Predicted Properties
Property Value Source
water solubility 1.98e-03 g/l ALOGPS
logP 3.10 ALOGPS
logP 3.64 ChemAxon Molconvert
logS -5.32 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 60.44 ChemAxon Molconvert
rotatable bond count 2 ChemAxon Molconvert
refractivity 113.50 ChemAxon Molconvert
polarizability 46.03 ChemAxon Molconvert
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00443 Link_out
KEGG Compound C07310 Link_out
PubChem Compound 5833 Link_out
PubChem Substance 46508525 Link_out
ChemSpider 5628 Link_out
BindingDB 50228080 Link_out
ChEBI 9241 Link_out
ChEMBL 9241 Link_out
Therapeutic Targets Database DAP000297 Link_out
PharmGKB PA451483 Link_out
HET SNL Link_out
Drug Product Database 613223 Link_out
RxList http://www.rxlist.com/cgi/generic/spiron.htm Link_out
Drugs.com http://www.drugs.com/spironolactone.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ald1010.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Spironolactone Link_out
ATC Codes
  • C03DA01
AHFS Codes
  • 24:32.20
PDB Entries Not Available
FDA label show (395 KB)
MSDS show (72.6 KB)
Interactions
Drug Interactions Not Available
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.
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. 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

Pharmacological action: unknown
Actions: antagonist

The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Activated, but not phosphorylated, by HIPK3

Organism class: human
UniProt ID: P10275 Link_out
Gene: AR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Enzymes

1. Cytochrome P450 2C8

Actions: inhibitor

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. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor, inducer

Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochrome P450 XIB

UniProt ID: P15538 Link_out
Gene: CYP11B1 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
Transporters

1. Canalicular multispecific organic anion transporter 1

Actions: inducer

Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter

UniProt ID: Q92887 Link_out
Gene: ABCC2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity)

UniProt ID: P46721 Link_out
Gene: SLCO1A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 April 19, 2011 15:03

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.