Chemistry:7α-Thiomethylspironolactone
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| Other names | 7α-TMS; SC-26519; 17α-Hydroxy-7α-(methylthio)-3-oxopregn-4-ene-21-carboxylic acid γ-lactone |
| Drug class | Antimineralocorticoid |
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| Formula | C23H32O3S |
| Molar mass | 388.57 g·mol−1 |
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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][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]
| Compound | Cmax (day 1) | Cmax (day 15) | AUC (day 15) | t1/2 |
|---|---|---|---|---|
| Spironolactone | 72 ng/mL (173 nmol/L) | 80 ng/mL (192 nmol/L) | 231 ng•hour/mL (555 nmol•hour/L) | 1.4 hours |
| Canrenone | 155 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-TMS | 359 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-TMS | 101 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
- ↑ 1.0 1.1 "Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences". Current Opinion in Pharmacology 27: 78–85. April 2016. doi:10.1016/j.coph.2016.02.005. PMID 26939027.
- ↑ "Mineralocorticoid receptor antagonists". Current Hypertension Reports 9 (1): 45–52. March 2007. doi:10.1007/s11906-007-0009-3. PMID 17362671.
- ↑ "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. doi:10.1530/JOE-16-0600. PMID 28634268.
- ↑ "The spironolactone renaissance". Expert Opinion on Investigational Drugs 10 (5): 943–954. May 2001. doi:10.1517/13543784.10.5.943. PMID 11322868.
- ↑ 5.0 5.1 "Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis". Heart Failure Reviews 10 (1): 23–29. January 2005. doi:10.1007/s10741-005-2345-1. PMID 15947888.
- ↑ 6.0 6.1 6.2 "Mineralocorticoid receptor antagonists and endothelial function". Current Opinion in Investigational Drugs 9 (9): 963–969. September 2008. PMID 18729003.
- ↑ "Pharmacological management of heart failure". Oxford Textbook of Medicine. 1. Oxford University Press. 2003. pp. 1–. ISBN 978-0-19-262922-7. https://books.google.com/books?id=_s65U1n9Lf8C&pg=RA1-PA962.
- ↑ 8.0 8.1 "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. doi:10.1210/jcem-47-1-171. PMID 263288.
- ↑ International Agency for Research on Cancer; World Health Organization (2001). Some Thyrotropic Agents. World Health Organization. pp. 325–. ISBN 978-92-832-1279-9. https://books.google.com/books?id=l965aqw_LSkC&pg=PA325.
- ↑ "A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone". Steroids 78 (1): 102–107. January 2013. doi:10.1016/j.steroids.2012.09.005. PMID 23063964.
- ↑ "Medical Treatment of Ascites in Cirrhosis". Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. John Wiley & Sons. 15 April 2008. p. 229. doi:10.1002/9780470987476.ch18. ISBN 978-1-4051-4370-7. https://www.academia.edu/download/42570322/Hepatorenal_Syndrome_in_Cirrhosis_Clinic20160211-3998-1be2rcb.pdf#page=234.
Further reading
- "Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites". Journal of Clinical Pharmacology 29 (4): 342–347. April 1989. doi:10.1002/j.1552-4604.1989.tb03339.x. PMID 2723123.
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