SPIRONOLACTONE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C24H32O4S
Molecular Weight	416.573
Optical Activity	UNSPECIFIED
Defined Stereocenters	7 / 7
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(=O)S[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H](CC[C@@]45CCC(=O)O5)[C@H]13

InChI

InChIKey=LXMSZDCAJNLERA-ZHYRCANASA-N

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

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00421
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/012151s072lbl.pdf

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. 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. Spironolactone is used primarily to treat low-renin hypertension, hypokalemia, and Conn's syndrome.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Mineralocorticoid receptor 53 Target ID: CHEMBL1994 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26073023	Antagonist 2849	11.0 nM [IC50]
Androgen Receptor 169 Target ID: CHEMBL1871 Sources: http://www.drugbank.ca/drugs/DB00421	Antagonist 2849	120.0 nM [IC50]
Progesterone receptor 61 Target ID: CHEMBL208 Sources: http://www.drugbank.ca/drugs/DB00421	Antagonist 2849	650.0 nM [IC50]
Glucocorticoid receptor 173 Target ID: CHEMBL2034 Sources: http://www.drugbank.ca/drugs/DB00421	Antagonist 2849	1.4 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Discrete aldosterone-producing adrenal adenomas 1 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/012151s072lbl.pdf	Primary	Approved 8583	ALDACTONE Approved Use ALDACTONE (spironolactone) is indicated in the management of: Primary hyperaldosteronism for: Establishing the diagnosis of primary hyperaldosteronism by therapeutic trial. Short-term preoperative treatment of patients with primary hyperaldosteronism. Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery. Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism). Edematous conditions for patients with: Congestive heart failure: For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures. ALDACTONE is also indicated for patients with congestive heart failure taking digitalis when other therapies are considered inappropriate. Cirrhosis of the liver accompanied by edema and/or ascites: Aldosterone levels may be exceptionally high in this condition. ALDACTONE is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium. Nephrotic syndrome: For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response. Essential hypertension ALDACTONE is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Hypokalemia For the treatment of patients with hypokalemia when other measures are considered inappropriate or inadequate. ALDACTONE is also indicated for the prophylaxis of hypokalemia in patients taking digitalis when other measures are considered inadequate or inappropriate. Severe heart failure (NYHA class III – IV) To increase survival, and to reduce the need for hospitalization for heart failure when used in addition to standard therapy. Launch Date 1960
Congestive heart failure 54 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/012151s072lbl.pdf	Primary	Approved 8583	ALDACTONE Approved Use ALDACTONE (spironolactone) is indicated in the management of: Primary hyperaldosteronism for: Establishing the diagnosis of primary hyperaldosteronism by therapeutic trial. Short-term preoperative treatment of patients with primary hyperaldosteronism. Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery. Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism). Edematous conditions for patients with: Congestive heart failure: For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures. ALDACTONE is also indicated for patients with congestive heart failure taking digitalis when other therapies are considered inappropriate. Cirrhosis of the liver accompanied by edema and/or ascites: Aldosterone levels may be exceptionally high in this condition. ALDACTONE is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium. Nephrotic syndrome: For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response. Essential hypertension ALDACTONE is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Hypokalemia For the treatment of patients with hypokalemia when other measures are considered inappropriate or inadequate. ALDACTONE is also indicated for the prophylaxis of hypokalemia in patients taking digitalis when other measures are considered inadequate or inappropriate. Severe heart failure (NYHA class III – IV) To increase survival, and to reduce the need for hospitalization for heart failure when used in addition to standard therapy. Launch Date 1960
Essential hypertension 17 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/012151s072lbl.pdf	Primary	Approved 8583	ALDACTONE Approved Use ALDACTONE (spironolactone) is indicated in the management of: Primary hyperaldosteronism for: Establishing the diagnosis of primary hyperaldosteronism by therapeutic trial. Short-term preoperative treatment of patients with primary hyperaldosteronism. Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery. Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism). Edematous conditions for patients with: Congestive heart failure: For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures. ALDACTONE is also indicated for patients with congestive heart failure taking digitalis when other therapies are considered inappropriate. Cirrhosis of the liver accompanied by edema and/or ascites: Aldosterone levels may be exceptionally high in this condition. ALDACTONE is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium. Nephrotic syndrome: For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response. Essential hypertension ALDACTONE is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Hypokalemia For the treatment of patients with hypokalemia when other measures are considered inappropriate or inadequate. ALDACTONE is also indicated for the prophylaxis of hypokalemia in patients taking digitalis when other measures are considered inadequate or inappropriate. Severe heart failure (NYHA class III – IV) To increase survival, and to reduce the need for hospitalization for heart failure when used in addition to standard therapy. Launch Date 1960

C_max

Value	Dose	Co-administered	Analyte	Population
47.4 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18488807	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		SPIRONOLACTONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
150.41 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18488807	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		SPIRONOLACTONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
2.37 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18488807	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		SPIRONOLACTONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1.4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012151s075lbl.pdf	unknown		SPIRONOLACTONE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
10% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012151s075lbl.pdf	unknown		SPIRONOLACTONE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
		CYP3A 142

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A 317	inducer 1966 Sources: https://pubmed.ncbi.nlm.nih.gov/12011477/ Page: 4.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.ahajournals.org/doi/10.1161/01.CIR.0000048189.58449.F7

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:9241	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9241
ChemicalBook	CB9743463	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9743463
eMolecules	29702936	https://www.emolecules.com/cgi-bin/more?vid=29702936
eMolecules	31590111	https://www.emolecules.com/cgi-bin/more?vid=31590111
eMolecules	594297	https://www.emolecules.com/cgi-bin/more?vid=594297
MolPort	MolPort-033-355-721	https://www.molport.com/shop/molecule-link/MolPort-033-355-721
Selleck Chemicals	spironolactone	http://www.selleckchem.com/products/spironolactone.html
ZINC	ZINC000003861599	http://zinc15.docking.org/substances/ZINC000003861599

PubMed

Title	Date	PubMed
Intrapatient comparison of treatment with chlorthalidone, spironolactone and propranolol in normoreninemic essential hypertension.	1975 Oct 31	1103606
Spironolactone-associated aggravation of renal functional impairment.	1976 Mar 10	1064790
The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.	1999 Sep 2	10471456
Induction of cardiac fibrosis by aldosterone.	2000 Jun	10888242
[White Paper of the Commission of European Community--strategy for a future chemicals policy].	2001	11378689
[Report on the ICCVAM workshop on in vitro methods for assessing acute systemic toxicity].	2001	11378685
The suitability of hepatocyte culture models to study various aspects of drug metabolism.	2001	11378681
[Good cell culture practice (GCCP)--an initiative for standardization and quality control of in vitro studies. The establishment of an ECVAM Task Force on GCCP].	2001	11248855
[In vitro models of intestinal and alveolar epithelium cultures in pharmaceutical research].	2001	11248854
[Mediator release assay of rat basophil leukemia cells as alternative for passive cutaneous anaphylaxis testing (PCA) in laboratory animals].	2001	11248853
[Effect of the preservative thiomersal on the release of interleukin-1 beta from human peripheral blood cells].	2001	11248851
[A new application for the human whole blood test: development of an assay to assess the health risk of air-borne microbial contaminations].	2001	11248850
[Recent developments on the European ban on animal experiments for cosmetics].	2001	11248844
Population-based investigation of relative clearance of digoxin in Japanese neonates and infants by multiple-trough screen analysis.	2001 Apr	11372585
Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications.	2001 Apr	11273866
[Effect of aldosterone on the secretion of endothelin by ventricular fibroblasts].	2001 Feb	11354792
Mineralocorticoid receptor-mediated signaling regulates the ion gated sodium channel in vascular endothelial cells and requires an intact cytoskeleton.	2001 Feb 9	11162670
Preformulation experiences and in vitro model studies with spironolactone-containing suppositories.	2001 Jan	11213791
Preventing acute mountain sickness.	2001 Jan	11195488
A very short synthesis of steroids from 1,3-butadiene and benzocyclobutenes.	2001 Jan 12	11429887
Inhibitors of type II 17beta-hydroxysteroid dehydrogenase.	2001 Jan 22	11165020
Quality control of inactivated erysipelas vaccines: results of an international collaborative study to establish a new regulatory test.	2001 Jan 8	11163671
Genotype/phenotype observations in African Americans with Bartter syndrome.	2001 Jul	11445802
Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats.	2001 Jul	11429393
Loop diuretic infusion increases thiazide-sensitive Na(+)/Cl(-)-cotransporter abundance: role of aldosterone.	2001 Jul	11423562
Psychological stress increases hippocampal mineralocorticoid receptor levels: involvement of corticotropin-releasing hormone.	2001 Jul 1	11425909
High serum level of procollagen type III amino-terminal peptide contributes to the efficacy of spironolactone and angiotensin-converting enzyme inhibitor therapy on left ventricular hypertrophy in essential hypertensive patients.	2001 Mar	11325081
Heart biometry and allometry in rats submitted to nitric oxide synthesis blockade and treatment with antihypertensive drugs.	2001 Mar	11325065
[Secondary hypertension].	2001 May	11391995
Diane 35 and spironolactone combination in the treatment of hirsutism.	2001 May	11380503
Breed and heterotic effects on postweaning traits in Altex and New Zealand White straightbred and crossbred rabbits.	2001 May	11374536
The spironolactone renaissance.	2001 May	11322868
Adrenocorticosteroid receptor blockade and excitotoxic challenge regulate adrenocorticosteroid receptor mRNA levels in hippocampus.	2001 May 1	11319772
Primary aldosteronism: a practical approach to diagnosis and treatment.	2001 May-Jun	11416708

Patents

Sample Use Guides

In Vivo Use Guide

Usual Adult Dose for Edema 25 to 200 mg/day orally in 1 or 2 divided doses. Usual Adult Dose for Hypertension 25 to 200 mg/day orally in 1 or 2 divided doses. Usual Adult Dose for Hypokalemia 25 to 200 mg/day orally in 1 or 2 divided doses. Usual Adult Dose for Primary Hyperaldosteronism Diagnosis 100 to 400 mg/day orally in 1 or 2 divided doses. Usual Adult Dose for Hirsutism 50 to 200 mg/day orally in 1 or 2 divided doses. Usual Adult Dose for Congestive Heart Failure 25 mg/day orally. Increase or decrease based on response and evidence of hyperkalemia. Usual Adult Dose for Primary Hyperaldosteronism Initial dose: 100 mg orally once a day. This dosage may be divided into two daily doses, and increased as tolerated every two to three days to a maximum recommended total daily dose of 400 mg.

Route of Administration: Oral

In Vitro Use Guide

Spironolactone (10 uM) abrogated MR agonist aldosterone-increased I (CaL) density in adult rat ventricular myocytes

Name

Type

Language

SPIRONOLACTONE

Official Name

English

ALDACTAZIDE COMPONENT SPIRONOLACTONE

Preferred Name

English

SPIRONOLACTONE [MART.]

Common Name

English

VEROSPIRONE

Common Name

English

17-Hydroxy-7?-mercapto-3-oxo-17?-pregn-4-ene-21-carboxylic acid, ?-lactone acetate

Common Name

English

SPIRONOLACTONE CEVA

Brand Name

English

SPIRONOLACTONE [IARC]

Common Name

English

ALDACTONE

Brand Name

English

SPIRONOLACTONUM [WHO-IP LATIN]

Common Name

English

Spironolactone [WHO-DD]

Common Name

English

SPIRONOLACTONE [JAN]

Common Name

English

SPIRONOLACTONE COMPONENT CARDALIS

Common Name

English

SPIRONOLACTONE [USP MONOGRAPH]

Common Name

English

SPIRONOLACTONE [WHO-IP]

Common Name

English

NSC-150399

Code

English

CARDALIS COMPONENT SPIRONOLACTONE

Brand Name

English

SPIRONOLACTONE [ORANGE BOOK]

Common Name

English

SPIRONOLACTONE [USP-RS]

Common Name

English

spironolactone [INN]

Common Name

English

SPIRONOLACTONE [MI]

Common Name

English

SPIRONOLACTONE [EMA EPAR VETERINARY]

Common Name

English

SPIRONOLACTONE [VANDF]

Common Name

English

PREGN-4-ENE-21-CARBOXYLIC ACID, 7-(ACETYLTHIO)-17-HYDROXY-3-OXO-,.GAMMA.-LACTONE, (7.ALPHA.,17.ALPHA.)-

Common Name

English

SPIRONOLACTONE [HSDB]

Common Name

English

SC-9420

Code

English

SPIRONOLACTONE [EP MONOGRAPH]

Common Name

English

Classification Tree Code System Code

WHO-ESSENTIAL MEDICINES LIST

16