Oxendolone

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Oxendolone
Oxendolone.svg
Clinical data
Trade names Prostetin, Roxenone
Synonyms TSAA-291; 16β-Ethyl-19-nortestosterone; 16β-Ethylestr-4-en-17β-ol-3-one
Routes of
administration
Intramuscular injection[1][2][3][4]
Drug class Steroidal antiandrogen; Progestin; Progestogen
Pharmacokinetic data
Bioavailability Oral: Very low (1% in dogs)[5]
Elimination half-life IM: 5.0–6.6 days.[4][6]
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C20H30O2
Molar mass 302.451 g/mol
3D model (JSmol)

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.[7][8][9][10][11] However, this use is controversial due to concerns about its clinical efficacy.[11] Oxendolone is not effective by mouth and must be given by injection into muscle.[5][1][2][3][4]

Oxendolone is an antiandrogen, and hence is an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone.[12][13][14][15][6] 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.[12][13][14][15] Due to its progestogenic activity, oxendolone has antigonadotropic effects.[16][17] Oxendolone has no other important hormonal activity.

Oxendolone was introduced for medical use in 1981.[8] It is used only in Japan.[8][11]

Medical uses[edit]

Oxendolone is used in the treatment of benign prostatic hyperplasia (BPH) in Japan.[8][11] It has been used at a dosage of 200 mg once every 2 weeks via intramuscular injection.[17] 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.[11]

Side effects[edit]

Pharmacology[edit]

Pharmacodynamics[edit]

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 (IC50 = 1.4 μM).[12][13][14][15] The binding affinity of oxendolone for the androgen receptor is far lower than that of cyproterone acetate.[6] At the androgen receptor, oxendolone is not a silent antagonist but is rather predominantly antagonistic with weak agonistic activity;[13] for this reason, it has been described as a selective androgen receptor modulator.[18] The drug has potent antigonadotropic effects via its progestogenic actions.[16] 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 dosages to treat BPH.[17]

Parenteral potencies of progestogens
Progestogen Type Class TFD
(14 days)
MDT
(week)
OID
(month)
POIC-D
(2–3 months)
CIC-D
(month)
Duration
Algestone acetophenide Synthetic Pregnane ND ND ND NA 75–150 mg ND
Gestonorone caproate Synthetic Norpregnane ND ND ND NA NA ND
Hydroxyprogesterone caproate Synthetic Pregnane 250–500 mg 25 mg 250–500 mg NA 250–500 mg 250 mg ≈ 10 days
Medroxyprogesterone acetate Synthetic Pregnane 50–100 mg ND ND 150 mg 25 mg 50 mg ≈ 14 days
Megestrol acetate Synthetic Pregnane ND ND ND NA 25 mg ND
Norethisterone enanthate Synthetic Estrane ND ND ND 200 mg 50 mg ND
Progesterone (oil soln.) Bioidentical Pregnane 200 mg ND ND NA NA 25 mg ≈ 2–3 days
Progesterone (cryst. susp.) Bioidentical Pregnane 50–100 mg ND ND NA NA 50 mg ≈ 14 days
Notes: All by intramuscular injection. Abbreviations: TFD = Endometrial transformation dose. MDT = Menstrual delay test dose (Greenblatt). OID = Ovulation-inhibiting dose (antigonadotropic effect; without an estrogen). POIC-D = Progestogen-only injectable contraceptive dose(s). CIC-D = Combined injectable contraceptive dose(s). Miscellaneous: Direct link to table. Sources:[19][20][21][22][23]

Pharmacokinetics[edit]

The oral bioavailability of oxendolone in dogs is extremely low, 1% at most.[5] Due to its low oral bioavailability, oxendolone is administered by intramuscular injection in humans.[1][2][3][4] Its elimination half-life via this route is 5.0 to 6.6 days.[4]

Chemistry[edit]

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).[7][8]

The acetate ester of oxendolone is known as TSAA-328, while the caproate ester of oxendolone is known as TSAA-330.[24] They were never marketed.[24]

History[edit]

Oxendolone has been marketed in Japan by Takeda since 1981.[8]

Society and culture[edit]

Generic names[edit]

Oxendolone is the generic name of the drug and its INN, USAN, and JAN.[7][25] It is also known by its developmental code name TSAA-291.[7][25]

Brand names[edit]

Oxendolone is or has been sold under the brand names Prostetin and Roxenone.[7][25]

Availability[edit]

Oxendolone is marketed only in Japan.[25]

References[edit]

  1. ^ a b c Henkler G, Klotzbach M, Koch H, Müller W, Richter J (1982). "[Progress in the area of drug development. 15]". Pharmazie (in German). 37 (11): 753–65. PMID 6131442. [Oxendolone] has been clinically tested in Japan (weekly intramuscular injection of 200-400 mg) in prostatic hypertrophy. 
  2. ^ a b c Hikichi Y, Yamaoka M, Kusaka M, Hara T (2015). "Selective androgen receptor modulator activity of a steroidal antiandrogen TSAA-291 and its cofactor recruitment profile". Eur. J. Pharmacol. 765: 322–31. doi:10.1016/j.ejphar.2015.08.052. PMID 26335395. 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). 
  3. ^ a b c Ostri P, Swartz R, Meyhoff HH, Petersen JH, Lindgård G, Frimodt-Møller C, Andersson T, Nielsen MS (1989). "Antiandrogenic treatment of benign prostatic hyperplasia: a placebo controlled trial". Urol. Res. 17 (1): 29–33. doi:10.1007/bf00261046. PMID 2466359. Thirty patients were treated with weekly injections of oxendolone 200 mg during a 3 months' period, and 30 patients were allocated to placebo treatment. 
  4. ^ a b c d e Midgley I, Fowkes AG, Darragh A, Lambe R, Chasseaud LF, Taylor T (1983). "The metabolic fate of the anti-androgenic agent, oxendolone, in man". Steroids. 41 (4): 521–36. doi:10.1016/0039-128x(83)90092-2. PMID 6419414. After intramuscular administration of 16β-ethyl-17β-hydroxy-4-[4-14C] estren-3-one (14C-oxendolone; 300 mg) to 3 human subjects, [...] 
  5. ^ a b c Michael J. Rathbone; Jonathan Hadgraft; Michael S. Roberts (7 November 2002). Modified-Release Drug Delivery Technology. CRC Press. pp. 368–. ISBN 978-0-8247-0869-6. 
  6. ^ a b c Gao, Wenqing; Bohl, Casey E.; Dalton, James T. (2005). "Chemistry and Structural Biology of Androgen Receptor". Chemical Reviews. 105 (9): 3352–3370. doi:10.1021/cr020456u. ISSN 0009-2665. PMC 2096617Freely accessible. PMID 16159155. 
  7. ^ a b c d e J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 914–. ISBN 978-1-4757-2085-3. 
  8. ^ a b c d e f William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 2935–. ISBN 978-0-8155-1856-3. 
  9. ^ Martin Negwer; Hans-Georg Scharnow (2001). Organic-chemical drugs and their synonyms: (an international survey). Wiley-VCH. p. 2023. ISBN 978-3-527-30247-5. 
  10. ^ Tan, MH Eileen; Li, Jun; Xu, H Eric; Melcher, Karsten; Yong, Eu-leong (2014). "Androgen receptor: structure, role in prostate cancer and drug discovery". Acta Pharmacologica Sinica. 36 (1): 3–23. doi:10.1038/aps.2014.18. ISSN 1671-4083. PMC 4571323Freely accessible. PMID 24909511. 
  11. ^ a b c d e Ishizuka, Osamu; Nishizawa, Osamu; Hirao, Yoshihiko; Ohshima, Shinichi (2002). "Evidence-based meta-analysis of pharmacotherapy for benign prostatic hypertrophy". International Journal of Urology. 9 (11): 607–612. doi:10.1046/j.1442-2042.2002.00539.x. ISSN 0919-8172. PMID 12534901. 
  12. ^ a b c Annual Reports in Medicinal Chemistry. Academic Press. 8 September 1989. pp. 199–. ISBN 978-0-08-058368-6. 
  13. ^ a b c d Annual report of Shionogi Research Laboratories. 1991. pp. 76–77. 
  14. ^ a b c Kirby, RogerS.; Christmas, Timothy (1991). "The potential value of 5-alpha-reductase inhibition in the treatment of bladder outflow obstruction due to benign prostatic hyperplasia". World Journal of Urology. 9 (1). doi:10.1007/BF00184713. ISSN 0724-4983. 
  15. ^ a b c Bashirelahi, N.; Ganesan, S.; Ekiko, D.B.; Young, J.D.; Shida, K.; Yamanaka, H.; Takahashi, E. (1986). "Effect of 16β-ethyl-17β-hydroxy-4-estren-3-one (tsaa-291) on the binding of promegestone (r5020) and methyltrienolone (r1881) to hyperplastic and neoplastic human prostate". Journal of Steroid Biochemistry. 25 (3): 367–374. doi:10.1016/0022-4731(86)90249-9. ISSN 0022-4731. 
  16. ^ a b Sudo, K.; Yamazaki, I.; Masuoka, M.; Nakayama, R. (1979). "IV. EFFECTS OF THE ANTI-ANDROGEN TSAA-291 (16 -ETHYL-17 -HYDROXY-4-OESTREN-3-ONE) ON THE SECRETION OF GONADOTROPHINS". European Journal of Endocrinology. 92 (3 Supplb): S53–S66. doi:10.1530/acta.0.092S053. ISSN 0804-4643. 
  17. ^ a b c Katayama T, Umeda K, Kazama T (November 1986). "[Hormonal environment and antiandrogenic treatment in benign prostatic hypertrophy]". Hinyokika Kiyo (in Japanese). 32 (11): 1584–9. PMID 2435122. 
  18. ^ Hikichi, Yukiko; Yamaoka, Masuo; Kusaka, Masami; Hara, Takahito (2015). "Selective androgen receptor modulator activity of a steroidal antiandrogen TSAA-291 and its cofactor recruitment profile". European Journal of Pharmacology. 765: 322–331. doi:10.1016/j.ejphar.2015.08.052. ISSN 0014-2999. PMID 26335395. 
  19. ^ Karl Knörr; Fritz K. Beller; Christian Lauritzen (17 April 2013). Lehrbuch der Gynäkologie. Springer-Verlag. pp. 214–. ISBN 978-3-662-00942-0. 
  20. ^ Karl Knörr; Henriette Knörr-Gärtner; Fritz K. Beller; Christian Lauritzen (8 March 2013). Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion. Springer-Verlag. pp. 583–. ISBN 978-3-642-95583-9. 
  21. ^ Sang GW (April 1994). "Pharmacodynamic effects of once-a-month combined injectable contraceptives". Contraception. 49 (4): 361–85. doi:10.1016/0010-7824(94)90033-7. PMID 8013220. 
  22. ^ Toppozada MK (April 1994). "Existing once-a-month combined injectable contraceptives". Contraception. 49 (4): 293–301. doi:10.1016/0010-7824(94)90029-9. PMID 8013216. 
  23. ^ Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S (2014). "Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control" (PDF). World J Pharm Pharm Sci. 3 (10): 364–392. ISSN 2278-4357. 
  24. ^ a b Masuoka M, Masaki T, Yamazaki I, Hori T, Nakayama R (1979). "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". Acta Endocrinol Suppl (Copenh). 229: 36–52. PMID 294106. 
  25. ^ a b c d https://www.drugs.com/international/oxendolone.html