page_title: Spironolactone
section_title: Metabolism
hierarchical_section_title: Spironolactone / Pharmacology / Pharmacokinetics / Metabolism
caption_attribution_description: English: Metabolic pathways of spironolactone in humans. Sources of the information: &#32;(February 1992).&#32;"High-performance liquid chromatographic determination of spironolactone and its metabolites in human biological fluids after solid-phase extraction". J. Chromatogr.&#32;574&#32;(1): 57–64. DOI:10.1016/0378-4347(92)80097-A. PMID 1629288. &#32;(1989).&#32;"Canrenone formation via general-base-catalyzed elimination of 7 alpha-(methylthio)spironolactone S-oxide". Chem. Res. Toxicol.&#32;2&#32;(2): 109–13. DOI:10.1021/tx00008a007. PMID 2519709. December 2012 Diuretics, Springer Science &amp; Business Media, pp.&#160;194– ISBN&#58; 978-3-642-79565-7.&#32; &#32;Spironolactone[1], volume 29, 2002, DOI:10.1016/S1075-6280(02)29009-6, ISSN 10756280, pages 261–320 &#32;(1976).&#32;"Pharmacokinetics of spironolactone in man". Naunyn-Schmiedeberg's Archives of Pharmacology&#32;296&#32;(1): 37–45. DOI:10.1007/BF00498838. ISSN 0028-1298. &#32;(1987).&#32;"The metabolism and biopharmaceutics of spironolactone in man". Rev Drug Metab Drug Interact&#32;5&#32;(4): 273–302. DOI:10.1515/DMDI.1987.5.4.273. PMID 3333882.
context_page_description: Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women, and as a part of transgender hormone therapy in transgender women. Spironolactone is taken by mouth.
  Common side effects include electrolyte abnormalities, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex. In those with liver or kidney problems, extra care should be taken. Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy. It is a steroid that blocks the effects of the hormones aldosterone and testosterone and has some estrogen-like effects. Spironolactone belongs to a class of medications known as potassium-sparing diuretics.
  Spironolactone was discovered in 1957, and was introduced in 1959. It is on the World Health Organization's List of Essential Medicines.
context_section_description: Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a very short terminal half-life of 1.4 hours. The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ⁶-spironolactone). These metabolites have much longer elimination half-lives than spironolactone of 13.8 hours, 15.0 hours, and 16.5 hours, respectively, and are responsible for the therapeutic effects of the medication. As such, spironolactone is a prodrug. The 7α-thiomethylated metabolites of spironolactone were not known for many years and it was originally thought that canrenone was the major active metabolite of the medication, but subsequent research identified 7α-TMS as the major metabolite. Other known but more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), which is an important intermediate to the major metabolites of spironolactone, as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.
  Spironolactone is hydrolyzed or deacetylated at the thioester of the C7α position into 7α-TS by carboxylesterases. Following formation of 7α-TS, it is S-oxygenated by flavin-containing monooxygenases to form an electrophilic sulfenic acid metabolite. This metabolite is involved in the CYP450 inhibition of spironolactone, and also binds covalently to other proteins. 7α-TS is also S-methylated into 7α-TMS, a transformation catalyzed by thiol S-methyltransferase. Unlike the related medication eplerenone, spironolactone is said to not be metabolized by CYP3A4. However, hepatic CYP3A4 is likely responsible for the 6β-hydroxylation of 7α-TMS into 6β-OH-7α-TMS. 7α-TMS may also be hydroxylated at the C3α and C3β positions. Spironolactone is dethioacetylated into canrenone. Finally, the C17 γ-lactone ring of spironolactone is hydrolyzed by the paraoxonase PON3. It was originally thought to be hydrolyzed by PON1, but this was due to contamination with PON3.
caption: Spironolactone metabolism in humans.[232] Canrenone may be further reduced (into di-, tetra-, and hexahydrogenated metabolites), hydroxylated, and conjugated (e.g., glucuronidated).[232]
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