7α-Thiomethylspironolactone explained

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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] [4] [5]}

Spironolactone is a prodrug with a short terminal half-life of 1.4 hours.^{[6] [7] [8]} 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.

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.^[9] 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).

7α-TMS has been found to account for around 80% of the potassium-sparing effect of spironolactone,^{[10] [11] [12]} whereas canrenone accounts for the remaining approximate 10 to 25% of the potassium-sparing effect of the drug.^[13]

See also

• 7α-Thiomethylspironolactone sulfoxide
• 7α-Thioprogesterone

Further reading

• Gardiner P, Schrode K, Quinlan D, Martin BK, Boreham DR, Rogers MS, Stubbs K, Smith M, Karim A . 6 . Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites . Journal of Clinical Pharmacology . 29 . 4 . 342–347 . April 1989 . 2723123 . 10.1002/j.1552-4604.1989.tb03339.x . 29457093 .

Notes and References

1. Yang J, Young MJ . Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences . Current Opinion in Pharmacology . 27 . 78–85 . April 2016 . 26939027 . 10.1016/j.coph.2016.02.005 .
2. Parthasarathy HK, MacDonald TM . Mineralocorticoid receptor antagonists . Current Hypertension Reports . 9 . 1 . 45–52 . March 2007 . 17362671 . 10.1007/s11906-007-0009-3 . 2090391 .
3. Kolkhof P, Bärfacker L . 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development . The Journal of Endocrinology . 234 . 1 . T125–T140 . July 2017 . 28634268 . 5488394 . 10.1530/JOE-16-0600 .
4. Yang J, Young MJ . Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences . Current Opinion in Pharmacology . 27 . 78–85 . April 2016 . 26939027 . 10.1016/j.coph.2016.02.005 .
5. Doggrell SA, Brown L . The spironolactone renaissance . Expert Opinion on Investigational Drugs . 10 . 5 . 943–954 . May 2001 . 11322868 . 10.1517/13543784.10.5.943 . 39820875 .
6. Sica DA . Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis . Heart Failure Reviews . 10 . 1 . 23–29 . January 2005 . 15947888 . 10.1007/s10741-005-2345-1 . 21437788 .
7. Maron BA, Leopold JA . Mineralocorticoid receptor antagonists and endothelial function . Current Opinion in Investigational Drugs . 9 . 9 . 963–969 . September 2008 . 18729003 . 2967484 .
8. Book: Aronson JK . Pharmacological management of heart failure . Warrel DA, Cox TM, Firth JD, Benz Jr EJ . Oxford Textbook of Medicine . 1 . https://books.google.com/books?id=_s65U1n9Lf8C&pg=RA1-PA962. 2003. Oxford University Press. 978-0-19-262922-7. 1–.
9. Cutler GB, Pita JC, Rifka SM, Menard RH, Sauer MA, Loriaux DL . SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate . The Journal of Clinical Endocrinology and Metabolism . 47 . 1 . 171–175 . July 1978 . 263288 . 10.1210/jcem-47-1-171 .
10. Maron BA, Leopold JA . Mineralocorticoid receptor antagonists and endothelial function . Current Opinion in Investigational Drugs . 9 . 9 . 963–969 . September 2008 . 18729003 . 2967484 .
11. Book: International Agency for Research on Cancer. World Health Organization. Some Thyrotropic Agents. 2001. World Health Organization. 978-92-832-1279-9. 325–.
12. Agusti G, Bourgeois S, Cartiser N, Fessi H, Le Borgne M, Lomberget T . A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone . Steroids . 78 . 1 . 102–107 . January 2013 . 23063964 . 10.1016/j.steroids.2012.09.005 . 8992318 .
13. Book: Angeli P, Gatta A . Medical Treatment of Ascites in Cirrhosis . Ginés P, Arroyo V, Rodés J, Schrier RW . Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment . 15 April 2008. John Wiley & Sons. 978-1-4051-4370-7 . 10.1002/9780470987476.ch18 . 229 . https://www.academia.edu/download/42570322/Hepatorenal_Syndrome_in_Cirrhosis_Clinic20160211-3998-1be2rcb.pdf#page=234 .