Oxendolone

{{Short description|Chemical compound}} {{Distinguish|Oxandrolone}} {{Drugbox | Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = (9''S'',14''S'',17''S'')-16-ethyl-17-hydroxy-13-methyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1''H''-cyclopenta[''a'']phenanthren-3-one | image = Oxendolone.svg | image_class = skin-invert-image | width = 225px

| bioavailability = Oral: Very low (1% in dogs)<ref name="RathboneHadgraft2002" /> | protein_bound = | metabolism = | elimination_half-life = {{abbrlink|IM|Intramuscular injection}}: 5.0–6.6 days.<ref name="pmid6419414" /><ref name="GaoBohl2005">{{cite journal | vauthors = Gao W, Bohl CE, Dalton JT | title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–3370 | date = September 2005 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u }}</ref> | excretion =

| CAS_number_Ref = | CAS_number = 33765-68-3 | CAS_supplemental = | UNII_Ref = {{fdacite|correct|FDA}} | UNII = MN4I850D4P | ATC_prefix = | ATC_suffix = | PubChem = 36592 | DrugBank_Ref = | DrugBank = | ChemSpiderID_Ref = | ChemSpiderID = 392001 | synonyms = TSAA-291; 16β-Ethyl-19-nortestosterone; 16β-Ethylestr-4-en-17β-ol-3-one

| C=20 | H=30 | O=2 | SMILES = CCC1CC2C3CCC4=CC(=O)CCC4C3CCC2(C1O)C | StdInChI_Ref = | StdInChI = 1S/C20H30O2/c1-3-12-11-18-17-6-4-13-10-14(21)5-7-15(13)16(17)8-9-20(18,2)19(12)22/h10,12,15-19,22H,3-9,11H2,1-2H3/t12?,15?,16-,17?,18+,19+,20?/m1/s1 | StdInChIKey_Ref = | StdInChIKey = FCKLFGKATYPJPG-LNRSQMQGSA-N }}  '''Oxendolone''', sold under the brand names '''Prostetin''' and '''Roxenone''', is an antiandrogen and progestin medication which is used in Japan in the treatment of enlarged prostate.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA914|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=914–}}</ref><ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA2935-IA129|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=2935–}}</ref><ref name="NegwerScharnow2001">{{cite book| vauthors = Negwer M, Scharnow HG |title=Organic-chemical drugs and their synonyms: (an international survey)|url=https://books.google.com/books?id=zmpqAAAAMAAJ|year=2001|publisher=Wiley-VCH|isbn=978-3-527-30247-5|page=2023}}</ref><ref name="TanLi2014">{{cite journal | vauthors = Tan MH, Li J, Xu HE, Melcher K, Yong EL | title = Androgen receptor: structure, role in prostate cancer and drug discovery | journal = Acta Pharmacologica Sinica | volume = 36 | issue = 1 | pages = 3–23 | date = January 2015 | pmid = 24909511 | pmc = 4571323 | doi = 10.1038/aps.2014.18 }}</ref><ref name="IshizukaNishizawa2002">{{cite journal | vauthors = Ishizuka O, Nishizawa O, Hirao Y, Ohshima S | title = Evidence-based meta-analysis of pharmacotherapy for benign prostatic hypertrophy | journal = International Journal of Urology | volume = 9 | issue = 11 | pages = 607–612 | date = November 2002 | pmid = 12534901 | doi = 10.1046/j.1442-2042.2002.00539.x | doi-access = free }}</ref> However, this use is controversial due to concerns about its clinical efficacy.<ref name="IshizukaNishizawa2002" /> Oxendolone is not effective by mouth and must be given by injection into muscle.<ref name="RathboneHadgraft2002" /><ref name="pmid6131442" /><ref name="pmid26335395" /><ref name="pmid2466359" /><ref name="pmid6419414" />

Oxendolone is an antiandrogen, and hence is an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone.<ref name="AcademicPress1989" /><ref name="Shinogi1991" /><ref name="KirbyChristmas1991" /><ref name="BashirelahiGanesan1986" /><ref name="GaoBohl2005" /> It is also a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.<ref name="AcademicPress1989" /><ref name="Shinogi1991" /><ref name="KirbyChristmas1991" /><ref name="BashirelahiGanesan1986" /> Due to its progestogenic activity, oxendolone has antigonadotropic effects.<ref name="SudoYamazaki1979" /><ref name="pmid2435122" /> Oxendolone has no other important hormonal activity...

Oxendolone was introduced for medical use in 1981.<ref name="Publishing2013" /> It is used only in Japan.<ref name="Publishing2013" /><ref name="IshizukaNishizawa2002" />

==Medical uses== Oxendolone is used in the treatment of benign prostatic hyperplasia (BPH) in Japan.<ref name="Publishing2013" /><ref name="IshizukaNishizawa2002" /> It has been used at a dosage of 200 mg once every 2 weeks via intramuscular injection.<ref name="pmid2435122">{{cite journal | vauthors = Katayama T, Umeda K, Kazama T | title = [Hormonal environment and antiandrogenic treatment in benign prostatic hypertrophy] | language = ja | journal = Hinyokika Kiyo. Acta Urologica Japonica | volume = 32 | issue = 11 | pages = 1584–1589 | date = November 1986 | pmid = 2435122 }}</ref> Although it is approved for the treatment of BPH in Japan, concerns have been raised about its use for this condition due to poor efficacy seen in clinical trials.<ref name="IshizukaNishizawa2002" />

==Side effects== {{See also|Antiandrogen#Side effects|Progestin#Side effects}}

==Pharmacology==

===Pharmacodynamics=== Oxendolone binds to the androgen receptor (Ki = 320 nM) and progesterone receptor (Ki = 20 nM) and acts as a weak but clinically relevant inhibitor of 5α-reductase ({{abbrlink|IC50|half-maximal inhibitory concentration}} = 1.4 μM).<ref name="AcademicPress1989">{{cite book | vauthors = Mallamo JP, Juniewicz PE | chapter = New horizons in the treatment of proliferative prostatic disease | veditors = Johns WS |title=Annual Reports in Medicinal Chemistry | chapter-url = https://books.google.com/books?id=HrALiG-4t7UC&pg=PA199 |date=8 September 1989| volume = 24 |publisher=Academic Press|isbn=978-0-08-058368-6|pages=199– | doi = 10.1016/S0065-7743(08)60543-6 }}</ref><ref name="Shinogi1991">{{cite book|title=Annual report of Shionogi Research Laboratories|url=https://books.google.com/books?id=kR40AAAAIAAJ|year=1991|pages=76–77}}</ref><ref name="KirbyChristmas1991">{{cite journal| vauthors = Kirby RS, Christmas T |title=The potential value of 5-alpha-reductase inhibition in the treatment of bladder outflow obstruction due to benign prostatic hyperplasia|journal=World Journal of Urology|volume=9|issue=1|year=1991|issn=0724-4983|doi=10.1007/BF00184713|s2cid=38790542}}</ref><ref name="BashirelahiGanesan1986">{{cite journal | vauthors = Bashirelahi N, Ganesan S, Ekiko DB, Young JD, Shida K, Yamanaka H, Takahashi E | title = Effect of 16 beta-ethyl-17 beta-hydroxy-4-estren-3-one (TSAA-291) on the binding of promegestone (R5020) and methyltrienolone (R1881) to hyperplastic and neoplastic human prostate | journal = Journal of Steroid Biochemistry | volume = 25 | issue = 3 | pages = 367–374 | date = September 1986 | pmid = 2430141 | doi = 10.1016/0022-4731(86)90249-9 }}</ref> The relative binding affinity of oxendolone for the androgen receptor is 0.8 to 3.6% of that of metribolone.<ref name="DaltonGao2010">{{cite book | vauthors = Dalton J, Gao W | chapter = Androgen Receptor|year=2010|pages=143–182|doi=10.1007/978-90-481-3303-1_6| title = Nuclear Receptors: Current Concepts and Future Challenges | series = Proteins and Cell Regulation| publisher = Springer|isbn=978-90-481-3302-4}}</ref><ref name="pmid7339263">{{cite journal | vauthors = Wakeling AE, Furr BJ, Glen AT, Hughes LR | title = Receptor binding and biological activity of steroidal and nonsteroidal antiandrogens | journal = Journal of Steroid Biochemistry | volume = 15 | pages = 355–359 | date = December 1981 | pmid = 7339263 | doi = 10.1016/0022-4731(81)90297-1 }}</ref> Oxendolone is not a silent antagonist of the androgen receptor but is rather predominantly antagonistic with weak agonistic activity;<ref name="Shinogi1991" /> for this reason, it has been described as a selective androgen receptor modulator.<ref name="HikichiYamaoka2015">{{cite journal | vauthors = Hikichi Y, Yamaoka M, Kusaka M, Hara T | title = Selective androgen receptor modulator activity of a steroidal antiandrogen TSAA-291 and its cofactor recruitment profile | journal = European Journal of Pharmacology | volume = 765 | pages = 322–331 | date = October 2015 | pmid = 26335395 | doi = 10.1016/j.ejphar.2015.08.052 }}</ref> The medication has potent antigonadotropic effects via its progestogenic activity.<ref name="SudoYamazaki1979">{{cite journal | vauthors = Sudo K, Yamazaki I, Masuoka M, Nakayama R | title = Anti-androgen TSAA-291. IV. Effects of the anti-androgen TSAA-291 (16 beta-ethyl-17 beta-hydroxy-4-oestren-3-one) on the secretion of gonadotrophins | journal = Acta Endocrinologica. Supplementum | volume = 229 | issue = 3 Supplb | pages = 53–66 | year = 1979 | pmid = 294107 | doi = 10.1530/acta.0.092S053 }}</ref> It has been found to suppress luteinizing hormone and testosterone levels to an equivalent extent as allylestrenol and chlormadinone acetate, which are two progestins that are similarly used at high doses to treat BPH.<ref name="pmid2435122" />

===Pharmacokinetics=== The oral bioavailability of oxendolone in dogs is extremely low, 1% at most.<ref name="RathboneHadgraft2002">{{cite book| vauthors = Iga K | chapter = Slowly Disintegrating Buccal Mucoadhesive Pain-Tablet (S-DBMP-T) and Buccal Covered=Tablet System (BCTS) | veditors = Rathbone MJ, Hadgraft J, Roberts MS |title=Modified-Release Drug Delivery Technology | chapter-url = https://books.google.com/books?id=mw9W82MLYZ8C&pg=PA368 |date=7 November 2002|publisher=CRC Press|isbn=978-0-8247-0869-6|pages=368–}}</ref> Due to its low oral bioavailability, oxendolone is administered by intramuscular injection in humans.<ref name="pmid6131442">{{cite journal | vauthors = Henkler G, Klotzbach M, Koch H, Müller W, Richter J | title = [Progress in the area of drug development. 15] | language = de | journal = Die Pharmazie | volume = 37 | issue = 11 | pages = 753–765 | date = November 1982 | pmid = 6131442 | quote = [Oxendolone] has been clinically tested in Japan (weekly intramuscular injection of 200-400 mg) in prostatic hypertrophy. }}</ref><ref name="pmid26335395">{{cite journal | vauthors = Hikichi Y, Yamaoka M, Kusaka M, Hara T | title = Selective androgen receptor modulator activity of a steroidal antiandrogen TSAA-291 and its cofactor recruitment profile | journal = European Journal of Pharmacology | volume = 765 | pages = 322–331 | date = October 2015 | pmid = 26335395 | doi = 10.1016/j.ejphar.2015.08.052 | quote = According to the clinical data of TSAA-291, the plasma level of TSAA-291 after weekly intramuscular administration at 400 mg/kg for 12 weeks is approximately 100 nM (Drug Information). }}</ref><ref name="pmid2466359">{{cite journal | vauthors = Ostri P, Swartz R, Meyhoff HH, Petersen JH, Lindgård G, Frimodt-Møller C, Andersson T, Nielsen MS | display-authors = 6 | title = Antiandrogenic treatment of benign prostatic hyperplasia: a placebo controlled trial | journal = Urological Research | volume = 17 | issue = 1 | pages = 29–33 | year = 1989 | pmid = 2466359 | doi = 10.1007/bf00261046 | quote = Thirty patients were treated with weekly injections of oxendolone 200 mg during a 3 months' period, and 30 patients were allocated to placebo treatment. | s2cid = 30551043 }}</ref><ref name="pmid6419414">{{cite journal | vauthors = Midgley I, Fowkes AG, Darragh A, Lambe R, Chasseaud LF, Taylor T | title = The metabolic fate of the anti-androgenic agent, oxendolone, in man | journal = Steroids | volume = 41 | issue = 4 | pages = 521–536 | date = April 1983 | pmid = 6419414 | doi = 10.1016/0039-128x(83)90092-2 | quote = After intramuscular administration of 16β-ethyl-17β-hydroxy-4-[4-14C] estren-3-one (14C-oxendolone; 300 mg) to 3 human subjects, [...] | s2cid = 41224726 }}</ref> Its elimination half-life via this route is 5.0 to 6.6 days.<ref name="pmid6419414" />

==Chemistry== {{See also|List of progestogens|Steroidal antiandrogen|List of steroidal antiandrogens}}

Oxendolone, also known as 16β-ethyl-19-nortestosterone or 16β-ethylestr-4-en-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone and 19-nortestosterone (nandrolone).<ref name="Elks2014" /><ref name="Publishing2013" />

The acetate ester of oxendolone is known as TSAA-328, while the caproate ester of oxendolone is known as TSAA-330.<ref name="pmid294106">{{cite journal | vauthors = Masuoka M, Masaki T, Yamazaki I, Hori T, Nakayama R | title = Anti-androgen TSAA-291. III. Hormonal spectra of anti-androgen TSAA-291 (16 beta-ethyl-17 beta-hydroxy-4-oestren-3-one) and its derivatives | journal = Acta Endocrinologica. Supplementum | volume = 229 | pages = 36–52 | year = 1979 | pmid = 294106 | doi = 10.1530/acta.0.092s036 }}</ref> They were never marketed.<ref name="pmid294106" />

==History== Oxendolone has been marketed in Japan by Takeda since 1981.<ref name="Publishing2013" />

==Society and culture==

===Generic names=== ''Oxendolone'' is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014" /><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/oxendolone.html|title=Oxandrolone Uses, Side Effects & Warnings | work = Drugs.com }}</ref> It is also known by its developmental code name ''TSAA-291''.<ref name="Elks2014" /><ref name="Drugs.com" />

===Brand names=== Oxendolone is or has been sold under the brand names Prostetin and Roxenone.<ref name="Elks2014" /><ref name="Drugs.com" />

===Availability=== Oxendolone is marketed only in Japan.<ref name="Drugs.com" />

== References == {{Reflist}}

{{Navboxes | title = Medical uses | titlestyle = background:#ccccff | list1 = {{Androgens and antiandrogens}} {{Progestogens and antiprogestogens}} {{Drugs used in benign prostatic hypertrophy}} }} {{Navboxes | title = Pharmacodynamics | titlestyle = background:#ccccff | list1 = {{Androgen receptor modulators}} {{Progesterone receptor modulators}} }}

Category:5α-Reductase inhibitors Category:Secondary alcohols Category:Antigonadotropins Category:Drugs for benign prostatic hyperplasia Category:Estranes Category:Ketones Category:Progestogens Category:Steroidal antiandrogens