7α-Thiomethylspironolactone

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7α-Thiomethylspironolactone
7α-Thiomethylspironolactone.svg
Clinical data
Synonyms 7α-TMS; SC-26519; 17α-Hydroxy-7α-(methylthio)-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
Drug class Antimineralocorticoid
Identifiers
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C23H32O3S
Molar mass 388.57 g·mol−1
3D model (JSmol)

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]

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 spironolactone and metabolites[9]
Compound Cmax (ng/mL)
(day 1)
Cmax (ng/mL)
(day 15)
AUC (ng•hr/ml)
(day 15)
t1/2 (hr)
Spironolactone 72 80 231 1.4
Canrenone 155 181 2173 16.5
7α-TMS 359 391 2804 13.8
6β-OH-7α-TMS 101 125 1727 15.0

7α-TMS has been found to account for around 80% of the potassium-sparing effect of spironolactone,[6][10][11] whereas canrenone accounts for the remaining approximate 10 to 25% of the potassium-sparing effect of the drug.[12]

See also[edit]

References[edit]

  1. ^ a b 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. PMID 17362671. 
  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 5488394Freely accessible. 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. 
  5. ^ a b 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. 
  6. ^ a b c Maron BA, Leopold JA (2008). "Mineralocorticoid receptor antagonists and endothelial function". Curr Opin Investig Drugs. 9 (9): 963–9. PMC 2967484Freely accessible. PMID 18729003. 
  7. ^ Oxford Textbook of Medicine: Vol. 1. Oxford University Press. 2003. pp. 1–. ISBN 978-0-19-262922-7. 
  8. ^ a b 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. ^ 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. PMID 2723123. 
  10. ^ International Agency for Research on Cancer; World Health Organization (2001). Some Thyrotropic Agents. World Health Organization. pp. 325–. ISBN 978-92-832-1279-9. 
  11. ^ 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. 
  12. ^ 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[edit]

  • 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. PMID 2723123.