CANRENONE

Possibly Marketed Outside US

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H28O3
Molecular Weight	340.4559
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@]34C)[C@@H]1CC[C@@]25CCC(=O)O5

InChI

InChIKey=UJVLDDZCTMKXJK-WNHSNXHDSA-N

InChI=1S/C22H28O3/c1-20-9-5-15(23)13-14(20)3-4-16-17(20)6-10-21(2)18(16)7-11-22(21)12-8-19(24)25-22/h3-4,13,16-18H,5-12H2,1-2H3/t16-,17+,18+,20+,21+,22-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/2761494 | http://www.my-personaltrainer.it/Foglietti-illustrativi/Luvion.html | https://www.ncbi.nlm.nih.gov/pubmed/25319120

Canrenone, a spironolactone metabolite, is a mineralocorticoid receptor antagonist. Canrenone is used as a diuretic in Europe and, in particular, in Italy under brand name Luvion. Luvion is a tablet for oral application which is effective for the treatment Hyperaldosteronism primary, secondary hyperaldosteronism from edematous states ( heart failure congestive, cirrhosis of the liver in phase ascites, nephrotic syndrome) and arterial hypertension essential where other therapies were not sufficiently effective or tolerate. In addition was suggested that canrenone might represent an effective therapy for idiopathic post-puberal hirsutism and it normalizds the cardiac response to the postural challenge in patients with preascitic cirrhosis. Canrenone seems to be effective in reducing blood pressure in patients with metabolic syndrome. Moreover, canrenone seems also to improve MPO, Lp(a), and metalloproteinases in these patients.

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Mineralocorticoid receptor 53 Target ID: P08235 Gene ID: 4306.0 Gene Symbol: NR3C2 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/4280522	Antagonist 2849

Conditions

Condition	Modality	Highest Phase	Product
Hyperaldosteronism 1 Sources: http://www.my-personaltrainer.it/Foglietti-illustrativi/Luvion.html	Palliative	Approved 8583	Luvion Approved Use Unknown
Arterial hypertension 5 Sources: http://www.my-personaltrainer.it/Foglietti-illustrativi/Luvion.html	Palliative	Approved 8583	Luvion Approved Use Unknown
Idiopathic hirsutism 1 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2761494	Palliative	Not Provided 511	Unknown Approved Use Unknown
Metabolic syndrome 34 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25319120	Palliative	Not Provided 511	Unknown Approved Use Unknown
Preascitic cirrhosis 1 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12029629/	Palliative	Not Provided 511	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse events
200 mg 4 times / day multiple, oral Highest studied dose Dose: 200 mg, 4 times / day Route: oral Route: multiple Dose: 200 mg, 4 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/973942/	healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/973942/	Sources: https://pubmed.ncbi.nlm.nih.gov/973942/
200 mg single, intravenous Highest studied dose Dose: 200 mg Route: intravenous Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/32398047/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: unknown Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/32398047/	Sources: https://pubmed.ncbi.nlm.nih.gov/32398047/
2 % 1 times / day multiple, topical Recommended Dose: 2 %, 1 times / day Route: topical Route: multiple Dose: 2 %, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17680878/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/17680878/	Disc. AE: Allergic contact dermatitis... AEs leading to discontinuation/dose reduction: Allergic contact dermatitis Sources: https://pubmed.ncbi.nlm.nih.gov/17680878/

AEs

AE	Significance	Dose	Population
Allergic contact dermatitis	Disc. AE	2 % 1 times / day multiple, topical Recommended Dose: 2 %, 1 times / day Route: topical Route: multiple Dose: 2 %, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17680878/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/17680878/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2252 inducer 1087	inhibitor 2438	inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP1B1 1079 OATP1B3 961 CYP2C19 2057 CYP19A1 429 CYP1A2 2153	P-gp 2052 CYP11A1 3

Drug as perpetrator

Target	Modality	Activity
CYP19A1 430	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/13789#section=Biological-Test-Results Page: 10.0	inconclusive [IC50 18.8336 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/13789#section=Biological-Test-Results Page: 15.0	inconclusive [IC50 27.5404 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/13789#section=Biological-Test-Results Page: 4.0	no [IC50 3.8902 uM]
CYP1A2 2333	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/13789#section=Biological-Test-Results Page: 195.0	no
CYP2D6 2546	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/13789#section=Biological-Test-Results Page: 189.0	no
CYP3A4 2633	inducer 1966 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/13789#section=Biological-Test-Results Page: 185.0	no
OATP1B1 1095	inhibitor 4027 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwxNjk3NjY4IiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDE0NjMzNDUifX0=	weak [Inhibition 10 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/13789#section=Biological-Test-Results Page: 2.0	yes [IC50 1.0964 uM]
OATP1B3 970	inhibitor 4027 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwxNzQzMTIxIiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDE0NjMzNDUifX0=	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 2052	substrate 4014 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/13789#section=Biological-Test-Results Page: 11 \| 185	inconclusive
CYP11A1 3	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/27125452/	yes [Kd 72.5 uM]

PubMed

Title	Date	PubMed
Analytical issues in HPLC/MS/MS simultaneous assay of furosemide, spironolactone and canrenone in human plasma samples.	2010-09-05	20307949
A low concentration of ouabain (0.18 microg/kg) enhances hypertension in spontaneously hypertensive rats by inhibiting the Na+ pump and activating the renin-angiotensin system.	2010-08	20602018
Spironolactone and canrenone inhibit UGT2B7-catalyzed human liver and kidney microsomal aldosterone 18beta-glucuronidation: a potential drug interaction.	2010-07	20304966
A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness of aldosterone antagonists for postmyocardial infarction heart failure.	2010-05	20492762
Development and validation of a dried blood spot-LC-APCI-MS assay for estimation of canrenone in paediatric samples.	2010-03-15	20153705
Immunohistochemical localization of transforming growth factor β-1 and its relationship with collagen expression in advanced liver fibrosis due to biliary atresia.	2010	21694865
Effect of spironolactone, potassium canrenoate, and their common metabolite canrenone on Dimension Vista Digoxin Assay.	2010	21089173
Spironolactone attenuates experimental uremic cardiomyopathy by antagonizing marinobufagenin.	2009-12	19884563
Effect of canrenone and amiloride on the prooxidative effect induced by aldosterone in human mononuclear leukocytes in vitro.	2009-12	19509473
The negative inotropic action of canrenone is mediated by L-type calcium current blockade and reduced intracellular calcium transients.	2009-09	19663883
Overview of therapeutic drug monitoring.	2009-03	19270474
Anti-remodelling effect of canrenone in patients with mild chronic heart failure (AREA IN-CHF study): final results.	2009-01	19147459
Determination and pharmacokinetic study of hydrocodone in human plasma by liquid chromatography coupled with tandem mass spectrometry.	2009	19728188
Effect of spironolactone, potassium canrenoate and their common metabolite canrenone on serum digoxin measurement by digoxin III, a new digoxin immunoassay.	2008-12	18824952
High-performance liquid chromatography-diode array and electrospray-mass spectrometry analysis of non-allowed substances in cosmetic products for preventing hair loss and other hormone-dependent skin diseases.	2008-11-04	18656319
Matrix metalloproteinase gene delivery for liver fibrosis.	2008-02	17577645
Bioequivalence assessment of two formulations of spironolactone in Chinese healthy male volunteers.	2008	18488807
Effect of spironolactone on diuresis and urine sodium and potassium excretion in healthy dogs.	2007-11	18024236
Baseline characteristics of patients recruited in the AREA IN-CHF study (Antiremodelling Effect of Aldosterone Receptors Blockade with Canrenone in Mild Chronic Heart Failure).	2007-09	17700397
Allergic contact dermatitis produced by canrenone.	2007-09	17680878
Clinical trials update from Heart Rhythm 2007 and Heart Failure 2007: CARISMA, PREPARE, DAVID II, SAVE-PACE, PROTECT and AREA-IN-CHF.	2007-08	17644412
High-speed gas chromatography in doping control: fast-GC and fast-GC/MS determination of beta-adrenoceptor ligands and diuretics.	2006-12	17305237
Why are mineralocorticoid receptor antagonists cardioprotective?	2006-12	17075718
Antiangiogenic effects of spironolactone and other potassium-sparing diuretics in human umbilical vein endothelial cells and in fibrin gel chambers implanted in rats.	2006-11	17053542
Development and validation of an HPLC method for the determination of spironolactone and its metabolites in paediatric plasma samples.	2006-07-24	16510319
Effects of spironolactone on human blood mononuclear cells: mineralocorticoid receptor independent effects on gene expression and late apoptosis induction.	2006-05	16520746
[Effects of aldosterone receptor blocker therapy on cardiac remodeling].	2006-04-25	16633997
Simultaneous determination of spironolactone and its active metabolite canrenone in human plasma by HPLC-APCI-MS.	2006-04	16541392
A new enzyme-linked chemiluminescent immunosorbent digoxin assay is virtually free from interference of spironolactone, potassium canrenoate, and their common metabolite canrenone.	2006	16960898
Sodium pump alpha2 subunits control myogenic tone and blood pressure in mice.	2005-11-15	16166162
Stability of spironolactone in rat plasma: strict temperature control of blood and plasma samples is required in rat pharmacokinetic studies.	2005-06	15930762
Nongenomic effects of mineralocorticoid receptor activation in the cardiovascular system.	2005-05-03	15862816
[The AREA IN-CHF trial (antiremodeling effect of aldosterone receptors blockade with canrenone in mild chronic heart failure): rationale and design].	2005-05	15945301
[Tolerability and efficacy of aldosterone inhibition with canrenone in heart failure: the real-world experience of an outpatient heart failure clinic].	2005-05	15945300
The Met852 residue is a key organizer of the ligand-binding cavity of the human mineralocorticoid receptor.	2005-05	15716462
Diastolic dysfunction and diastolic heart failure: diagnostic, prognostic and therapeutic aspects.	2005-04-04	15807887
Nanosuspension formulations for low-soluble drugs: pharmacokinetic evaluation using spironolactone as model compound.	2005-03	15830727
Effects of aldosterone and mineralocorticoid receptor blockade on intracellular electrolytes.	2005-01	15947890
Simultaneous determination of beta-blocking agents and diuretics in doping analysis by liquid chromatography/mass spectrometry with scan-to-scan polarity switching.	2005	15584083
Aldosterone enhances renal calcium reabsorption by two types of channels.	2004-07	15200430
Cross reactivity due to positive canrenone interference.	2004-05	15082604
Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring.	2004-04-02	15061868
Effect of aldosterone and glycyrrhetinic acid on the protein expression of PAI-1 and p22(phox) in human mononuclear leukocytes.	2004-04	15070972
Safety of low-dose spironolactone administration in chronic haemodialysis patients.	2003-11	14551366
The renin-angiotensin-aldosterone system in patients with depression compared to controls--a sleep endocrine study.	2003-10-29	14585110
[Anti-angiogenic effects of aldosterone antagonists in the fibrin chamber in rats].	2003-08-30	12945230
A new turbidometric digoxin immunoassay on the ADVIA 1650 analyzer is free from interference by spironolactone, potassium canrenoate, and their common metabolite canrenone.	2003-08	12883233
Conventional and micellar liquid chromatography method development for danazol and validation in capsules.	2003-07-14	14565547
Effect of canrenone on the digitalis site of Na+/K(+)-ATPase in human placental membranes and in erythrocytes.	2003-07	12827023
Ouabain-inhibiting activity of aldosterone antagonists.	1995-01	7792794

Patents

Sample Use Guides

In Vivo Use Guide

In the majority of cases are sufficient 50-200 mg per day, divided into one or more daily doses. In severe cases this dosage resistant or can be raised to 300 mg or more, according to medical prescription.

Route of Administration: Oral

In Vitro Use Guide

Canrenone (in concentration range: 0-10000 nM) decreased [3H]-progesterone binding to isolated uterine cytosolic progesterone receptors. The inhibition was concentration-dependent. Canrenone (in concentration range: 0-25150 nM) did not alter [3H]-oestradiol binding to isolated uterine cytosolic oestrogen receptors. Canrenone inhibition of progesterone binding to isolated cytosolic receptors was strictly competitive: Kd (apparent dissociation constant for progesterone binding) was increased in a concentration-dependent manner by canrenone, whereas Bmax (maximal number of progesterone binding sites/mg cytosolic protein) was unaltered. There was marked cooperativity in progesterone binding at high canrenone and low progesterone concentrations. The implication is that canrenone alters the subunit interaction of the receptor protein. Kd for progesterone was 3.2 X 10(-9)M. Ki (the inhibition constant for canrenone with respect to progesterone binding) was 300 X 10(-9)M.

Name

Type

Language

SPIRONOLACTONE RELATED COMPOUND A

Preferred Name

English

CANRENONE

Official Name

English

17-Hydroxy-3-oxo-17?-pregna-4,6-diene-21-carboxylic acid ?-lactone

Common Name

English

Canrenone [WHO-DD]

Common Name

English

canrenone [INN]

Common Name

English

NSC-261713

Code

English

CANRENONE [MART.]

Common Name

English

2R)-3,4-DIHYDRO-5H-SPIRO(ANDROST-4,6-DIENE-17,2-FURAN)-3,5-DIONE

Systematic Name

English

17.ALPHA.-(2-CARBOXYETHYL)-17.BETA.-HYDROXYANDROSTA-4,6-DIEN-3-ONE LACTONE

Common Name

English

SPIRONOLACTONE IMPURITY F [EP IMPURITY]

Common Name

English

CANRENONE [USAN]

Common Name

English

PREGNA-4,6-DIENE-21-CARBOXYLIC ACID, 17-HYDROXY-3-OXO-, .GAMMA.-LACTONE (17.ALPHA.)-

Common Name

English

CANRENONE [MI]

Common Name

English

SC-9376

Code

English

SPIRONOLACTONE METABOLITE M1

Common Name

English

SPIRONOLACTONE RELATED COMPOUND A [USP-RS]

Common Name

English

Classification Tree Code System Code

WHO-ATC

C03DA03