7α-Thiomethylspironolactone

7α-Thiomethylspironolactone (7α-TMS; developmental code name SC-26519) is a steroidal antimineralocorticoid and antiandrogen of the spirolactone group and the major active metabolite of spironolactone.[1] Other important metabolites of spironolactone include 7α-thiospironolactone (7α-TS; SC-24813), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (SC-9376).[2][3][1][4]

7α-Thiomethylspironolactone
Clinical data
Other names7α-TMS; SC-26519; 17α-Hydroxy-7α-(methylthio)-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
Drug classAntimineralocorticoid
Identifiers
IUPAC name
  • (7R,8R,9S,10R,13S,14S,17R)-10,13-dimethyl-7-methylsulfanylspiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-17,5'-oxolane]-2',3-dione
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H32O3S
Molar mass388.57 g·mol−1
3D model (JSmol)
SMILES
  • C[C@]12CCC(=O)C=C1C[C@H]([C@@H]3[C@@H]2CC[C@]4([C@H]3CC[C@@]45CCC(=O)O5)C)SC
InChI
  • InChI=1S/C23H32O3S/c1-21-8-4-15(24)12-14(21)13-18(27-3)20-16(21)5-9-22(2)17(20)6-10-23(22)11-7-19(25)26-23/h12,16-18,20H,4-11,13H2,1-3H3/t16-,17-,18+,20+,21-,22-,23+/m0/s1
  • Key:FWRDLPQBEOKIRE-RJKHXGPOSA-N

Spironolactone is a prodrug with a short terminal half-life of 1.4 hours.[5][6][7] The active metabolites of spironolactone have extended terminal half-lives of 13.8 hours for 7α-TMS, 15.0 hours for 6β-OH-7α-TMS, and 16.5 hours for canrenone, and accordingly, these metabolites are responsible for the therapeutic effects of the drug.[5][6]

7α-TS and 7α-TMS have been found to possess approximately equivalent affinity for the rat ventral prostate androgen receptor (AR) relative to that of spironolactone.[8] The affinity of 7α-TS, 7α-TMS, and spironolactone for the rat prostate AR is about 3.0 to 8.5% of that of dihydrotestosterone (DHT).[8]

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.

7α-TMS has been found to account for around 80% of the potassium-sparing effect of spironolactone,[6][9][10] whereas canrenone accounts for the remaining approximate 10 to 25% of the potassium-sparing effect of the drug.[11]

See also

References
  1. Yang J, Young MJ (2016). "Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences". Curr Opin Pharmacol. 27: 78–85. doi:10.1016/j.coph.2016.02.005. PMID 26939027.
  2. Parthasarathy HK, MacDonald TM (2007). "Mineralocorticoid receptor antagonists". Curr. Hypertens. Rep. 9 (1): 45–52. doi:10.1007/s11906-007-0009-3. PMID 17362671. S2CID 2090391.
  3. Kolkhof P, Bärfacker L (2017). "30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development". J. Endocrinol. 234 (1): T125–T140. doi:10.1530/JOE-16-0600. PMC 5488394. PMID 28634268.
  4. Doggrell SA, Brown L (2001). "The spironolactone renaissance". Expert Opin Investig Drugs. 10 (5): 943–54. doi:10.1517/13543784.10.5.943. PMID 11322868. S2CID 39820875.
  5. Sica DA (2005). "Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis". Heart Fail Rev. 10 (1): 23–9. doi:10.1007/s10741-005-2345-1. PMID 15947888. S2CID 21437788.
  6. Maron BA, Leopold JA (2008). "Mineralocorticoid receptor antagonists and endothelial function". Curr Opin Investig Drugs. 9 (9): 963–9. PMC 2967484. PMID 18729003.
  7. Oxford Textbook of Medicine: Vol. 1. Oxford University Press. 2003. pp. 1–. ISBN 978-0-19-262922-7.
  8. Cutler GB, Pita JC, Rifka SM, Menard RH, Sauer MA, Loriaux DL (1978). "SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate". J. Clin. Endocrinol. Metab. 47 (1): 171–5. doi:10.1210/jcem-47-1-171. PMID 263288.
  9. International Agency for Research on Cancer; World Health Organization (2001). Some Thyrotropic Agents. World Health Organization. pp. 325–. ISBN 978-92-832-1279-9.
  10. 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.
  11. 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.

Further reading
  • 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.


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