Canrenone

Canrenone
Skeletal formula of canrenone
Ball-and-stick model of the canrenone molecule
Clinical data
Trade namesContaren, Luvion, Phanurane, Spiroletan
Other namesAldadiene;[1] SC-9376; RP-11614; 7α-Desthioacetyl-δ6-spironolactone; 6,7-Dehydro-7α-desthioacetylspironolactone; 17-Hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone
AHFS/Drugs.comInternational Drug Names
Drug classAntimineralocorticoid
ATC code
Pharmacokinetic data
Protein binding95%
Elimination half-life16.5 hours[2]
Identifiers
IUPAC name
  • 10,13-Dimethylspiro[2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-17,5'-oxolane]-2',3-dione
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.012.322
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Chemical and physical data
FormulaC22H28O3
Molar mass340.463 g·mol−1
3D model (JSmol)
SMILES
  • O=C5\C=C4\C=C/[C@@H]1[C@H](CC[C@]3([C@H]1CC[C@]32OC(=O)CC2)C)[C@@]4(C)CC5
InChI
  • 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 checkY
  • Key:UJVLDDZCTMKXJK-WNHSNXHDSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid[3][4] of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium.[5][6][7][8] It is also an important active metabolite of spironolactone, and partially accounts for its therapeutic effects.[9][2]

Medical uses

Canrenone is mainly used as a diuretic.

Canrenone has been found to be effective in the treatment of hirsutism in women.[10]

Heart failure

Two studies of canrenone in people with heart failure have shown a mortality benefit compared to placebo. In the evaluation which studied people with chronic heart failure (CHF), people that were treated with canrenone displayed a lower number of deaths compared to the placebo group, indicating a death and morbidity benefit of the medication.

One study compared 166 treated with canrenone to 336 given conventional therapy lasting 10 years. Differences in systolic and diastolic blood pressure was observed between both patient groups where, patients treated with canrenone, showed a lower blood pressure compared to conventional therapy. Uric acid was lower in the group treated with canrenone; however, no differences were seen in potassium, sodium, and brain natriuretic peptide (BNP) levels. Left ventricular mass was also lower in the group treated with canrenone and a greater progression of NYHA class was observed in the control group compared to patients treated with canrenone.[11]

Another study concluded that treatment with canrenone in patients with chronic heart failure improves diastolic function and further decreased BNP levels.[12]

Pharmacology

Pharmacodynamics

Canrenone is reportedly more potent as an antimineralocorticoid relative to spironolactone, but is considerably less potent and effective as an antiandrogen.[13][14] Similarly to spironolactone, canrenone inhibits steroidogenic enzymes such as 11β-hydroxylase, cholesterol side-chain cleavage enzyme, 17α-hydroxylase, 17,20-lyase, and 21-hydroxylase, but once again, is comparatively less potent in doing so.[15]

Pharmacokinetics

The elimination half-life of canrenone is about 16.5 hours.[2]

As a metabolite

Canrenone is an active metabolite of spironolactone, canrenoic acid, and potassium canrenoate, and is considered to be partially responsible for their effects.[9] It has been found to account for approximately 10 to 25% of the potassium-sparing effect of spironolactone,[16] whereas another metabolite, 7α-thiomethylspironolactone (7α-TMS), accounts for around 80% of the potassium-sparing effect of the drug.[17][18][19]

Pharmacokinetics of 100 mg/day spironolactone and its metabolites
CompoundCmax (day 1)Cmax (day 15)AUC (day 15)t1/2
Spironolactone72 ng/mL (173 nmol/L)80 ng/mL (192 nmol/L)231 ng•hour/mL (555 nmol•hour/L)1.4 hours
Canrenone155 ng/mL (455 nmol/L)181 ng/mL (532 nmol/L)2,173 ng•hour/mL (6,382 nmol•hour/L)16.5 hours
7α-TMS359 ng/mL (924 nmol/L)391 ng/mL (1,006 nmol/L)2,804 ng•hour/mL (7,216 nmol•hour/L)13.8 hours
6β-OH-7α-TMS101 ng/mL (250 nmol/L)125 ng/mL (309 nmol/L)1,727 ng•hour/mL (4,269 nmol•hour/L)15.0 hours
Sources: See template.

History

Canrenone was described and characterized in 1959.[5] It was introduced for medical use, in the form of potassium canrenoate (the potassium salt of canrenoic acid), by 1968.[20]

Society and culture

Generic names

Canrenone is the INN and USAN of the drug.[6][8]

Brand names

Canrenone has been marketed under the brand names Contaren, Luvion, Phanurane, and Spiroletan, among others.[5][8][20]

Availability

Canrenone appears to remain available only in Italy, although potassium canrenoate remains marketed in various other countries as well.[21][22]

See also

References

  1. ↑ Jürg Müller (6 December 2012). Regulation of Aldosterone Biosynthesis: Physiological and Clinical Aspects. Springer Science & Business Media. pp. 164–. ISBN 978-3-642-83120-1.
  2. 1 2 3 Gardiner P, Schrode K, Quinlan D, Martin BK, Boreham DR, Rogers MS, Stubbs K, Smith M, Karim A (1989). "Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites". J Clin Pharmacol. 29 (4): 342–7. doi:10.1002/j.1552-4604.1989.tb03339.x. PMID 2723123. S2CID 29457093.
  3. ↑ Losert, W; Casals-Stenzel, J; Buse, M (1985). "Progestogens with antimineralocorticoid activity". Arzneimittelforschung. 35 (2): 459–71. PMID 4039568.
  4. ↑ Fernandez, MD; Carter, GD; Palmer, TN (1983). "The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol". Br J Clin Pharmacol. 15 (1): 95–101. doi:10.1111/j.1365-2125.1983.tb01470.x. PMC 1427833. PMID 6849751.
  5. 1 2 3 J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 210–. ISBN 978-1-4757-2085-3.
  6. 1 2 Hill, R.A.; Makin, H.L.J.; Kirk, D.N.; Murphy, G.M. (23 May 1991). Dictionary of Steroids. CRC Press. pp. 656–. ISBN 978-0-412-27060-4.
  7. ↑ Romanelli, RG; Gentilini, P (May 2004). "Cross reactivity due to positive canrenone interference". Gut. 53 (5): 772–3. PMC 1774040. PMID 15082604.
  8. 1 2 3 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 167–. ISBN 978-3-88763-075-1.
  9. 1 2 Clark, Michelle A.; Harvey, Richard A.; Finkel, Richard; Rey, Jose A.; Whalen, Karen (15 December 2011). Pharmacology. Lippincott Williams & Wilkins. pp. 286–. ISBN 978-1-4511-1314-3.
  10. ↑ Sobbrio, GA; Granata, A; Panacea, A; Trimarchi, F (1989). "Effectiveness of short term canrenone treatment in idiopathic hirsutism". Minerva Endocrinol. 14 (2): 105–8. PMID 2761494.
  11. ↑ Derosa, G.; Maffioli, P.; Scelsi, L.; Bestetti, A.; Vanasia, M.; Cicero AFG; Spinardi, L.; Bentivenga, C.; Esposti, D. D.; Caprio, M.; Borghi, C.; Pitt, B.; Cosentino, E. (2019-03-01). "Canrenone on cardiovascular mortality in congestive heart failure: CanrenOne eFFects on cardiovascular mortality in patiEnts with congEstIve hearT failure: The COFFEE-IT study". Pharmacological Research. 141: 46–52. doi:10.1016/j.phrs.2018.11.037. ISSN 1043-6618. PMID 30502530. S2CID 54564252.
  12. ↑ Simone, G. de; Chinali, M.; Mureddu, G. F.; Cacciatore, G.; Lucci, D.; Latini, R.; Masson, S.; Vanasia, M.; Maggioni, A. P.; Boccanelli, A. (2011-10-01). "Effect of canrenone on left ventricular mechanics in patients with mild systolic heart failure and metabolic syndrome: The AREA-in-CHF study". Nutrition, Metabolism and Cardiovascular Diseases. 21 (10): 783–791. doi:10.1016/j.numecd.2010.02.012. ISSN 0939-4753. PMID 21939839.
  13. ↑ Coelingh Benni, H.J.T.; Vemer, H.M. (15 December 1990). Chronic Hyperandrogenic Anovulation. CRC Press. pp. 152–. ISBN 978-1-85070-322-8.
  14. ↑ Seldin, Donald W.; Giebisch, Gerhard H. (23 September 1997). Diuretic Agents: Clinical Physiology and Pharmacology. Academic Press. pp. 630–. ISBN 978-0-08-053046-8.
  15. ↑ Colby, HD (1981). "Chemical suppression of steroidogenesis". Environ. Health Perspect. 38: 119–27. doi:10.1289/ehp.8138119. PMC 1568425. PMID 6786868.
  16. ↑ Pere Ginés; Vicente Arroyo; Juan Rodés; Robert W. Schrier (15 April 2008). Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. John Wiley & Sons. p. 229. ISBN 978-1-4051-4370-7.
  17. ↑ Maron BA, Leopold JA (2008). "Mineralocorticoid receptor antagonists and endothelial function". Curr Opin Investig Drugs. 9 (9): 963–9. PMC 2967484. PMID 18729003.
  18. ↑ International Agency for Research on Cancer; World Health Organization (2001). Some Thyrotropic Agents. World Health Organization. pp. 325–. ISBN 978-92-832-1279-9.
  19. ↑ Agusti G, Bourgeois S, Cartiser N, Fessi H, Le Borgne M, Lomberget T (2013). "A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone". Steroids. 78 (1): 102–7. doi:10.1016/j.steroids.2012.09.005. PMID 23063964. S2CID 8992318.
  20. 1 2 William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 804–. ISBN 978-0-8155-1856-3.
  21. ↑ "List of Aldosterone receptor antagonists".
  22. ↑ "Potassium Uses, Side Effects & Interactions".
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