7α-Thiospironolactone

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

7α-Thiospironolactone
Clinical data
Other names7α-TS; SC-24813; Deacetylspironolactone; Mercaptospironolactone; 17α-Hydroxy-7α-mercapto-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
Drug classAntimineralocorticoid; Antiandrogen
Identifiers
IUPAC name
  • (7R,8R,9S,10R,13S,14S,17R)-10,13-Dimethyl-7-sulfanylspiro[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
FormulaC22H30O3S
Molar mass374.54 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)S
InChI
  • InChI=1S/C22H30O3S/c1-20-7-3-14(23)11-13(20)12-17(26)19-15(20)4-8-21(2)16(19)5-9-22(21)10-6-18(24)25-22/h11,15-17,19,26H,3-10,12H2,1-2H3/t15-,16-,17+,19+,20-,21-,22+/m0/s1
  • Key:NZCDWYJROUPYPT-NYTLBARGSA-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]

7α-TS, via a reactive metabolite formed by 17α-hydroxylase, is a suicide inhibitor of 17α-hydroxylase, and is thought to be involved in the inhibition of 17α-hydroxylase by spironolactone.[9][10][11]

Pharmacokinetics of spironolactone and metabolites[12]
CompoundCmax (ng/mL)
(day 1)		Cmax (ng/mL)
(day 15)		AUC (ng•hr/ml)
(day 15)		t1/2 (hr)
Spironolactone72802311.4
Canrenone155181217316.5
7α-TMS359391280413.8
6β-OH-7α-TMS101125172715.0

A study assessed the interaction of spironolactone and 7α-TS with sex hormone-binding globulin and found that they had very low affinity for this carrier protein.[13]

See also

References
  1. 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.
  2. 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.
  3. 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.
  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. Colby HD, O'Donnell JP, Flowers NL, Kossor DC, Johnson PB, Levitt M (April 1991). "Relationship between covalent binding to microsomal protein and the destruction of adrenal cytochrome P-450 by spironolactone". Toxicology. 67 (2): 143–54. doi:10.1016/0300-483X(91)90138-Q. PMID 2031249.
  10. Kossor DC, Kominami S, Takemori S, Colby HD (August 1991). "Role of the steroid 17 alpha-hydroxylase in spironolactone-mediated destruction of adrenal cytochrome P-450". Mol. Pharmacol. 40 (2): 321–5. PMID 1875914.
  11. Decker CJ, Rashed MS, Baillie TA, Maltby D, Correia MA (June 1989). "Oxidative metabolism of spironolactone: evidence for the involvement of electrophilic thiosteroid species in drug-mediated destruction of rat hepatic cytochrome P450". Biochemistry. 28 (12): 5128–36. doi:10.1021/bi00438a033. PMID 2765527.
  12. 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.
  13. Pugeat MM, Dunn JF, Nisula BC (1981). "Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma". J. Clin. Endocrinol. Metab. 53 (1): 69–75. doi:10.1210/jcem-53-1-69. PMID 7195405.

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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