Flutamide

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Flutamide
Flutamide structural formulae.png
Flutamide ball-and-stick.png
Systematic (IUPAC) name
2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a697045
Pregnancy
category
  • D
Legal status
  • (Prescription only)
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability >90%
Protein binding 94 to 96%
Excretion >90% via urine
Identifiers
CAS Registry Number 13311-84-7 YesY
ATC code L02BB01
PubChem CID: 3397
IUPHAR/BPS 6943
DrugBank DB00499 YesY
ChemSpider 3280 YesY
UNII 76W6J0943E YesY
KEGG D00586 YesY
ChEBI CHEBI:5132 YesY
ChEMBL CHEMBL806 YesY
Synonyms SCH-13521
Chemical data
Formula C11H11F3N2O3
Molecular mass 276.212 g/mol
 YesY (what is this?)  (verify)

Flutamide (INN, USAN, BAN) (brand names Eulexin, Cytomid, Cebatrol, Chimax, Drogenil, Eulexin, Flucinom, Flutamin, Fugerel, Niftolide, Sebatrol) is an synthetic, non-steroidal, pure antiandrogen used primarily to treat prostate cancer.[1] It acts as a silent antagonist of the androgen receptor (AR), competing with androgens such as testosterone and its powerful active metabolite dihydrotestosterone (DHT) for binding to ARs in the prostate gland. By doing so, it prevents them from stimulating the prostate cancer cells to grow. In addition to its use in prostate cancer, flutamide has been used to treat hyperandrogenism (excess androgen levels) in women, such as in those with polycystic ovary syndrome (PCOS), and hirsutism.[2] Flutamide has been largely replaced by newer non-steroidal antiandrogens, namely bicalutamide, due to better safety, tolerability, and pharmacokinetic profiles.[3][4]

Flutamide was first introduced into clinical use in 1975,[5] and was approved by the United States Food and Drug Administration for the treatment of metastatic prostate cancer in combination with a gonadotropin-releasing hormone (GnRH) analogue in 1989.[6]

Use[edit]

Prostate cancer[edit]

GnRH is released by the hypothalamus in a pulsatile fashion; this causes the anterior pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the testes to produce testosterone, which is metabolized to DHT by the enzyme 5α-reductase.

DHT, and to a significantly smaller extent, testosterone, stimulate prostate cancer cells to grow. Therefore, blocking these androgens can provide powerful treatment for prostate cancer, especially metastatic disease. Normally administered are GnRH analogues, such as leuprorelin or cetrorelix. Although GnRH agonists stimulate the same receptors that GnRH does, since they are present continuously and not in a pulsatile manner, they serve to inhibit the pituitary gland and therefore block the whole chain. However, they initially cause a surge in activity; this is not solely a theoretical risk but may cause the cancer to flare. Flutamide was initially used at the beginning of GnRH agonist therapy to block this surge, and it and other non-steroidal antiandrogens continue in this use. In contrast to GnRH agonists, GnRH antagonists don't cause an initial androgen surge, and are gradually replacing GnRH agonists in clinical use.[citation needed]

There have been studies to investigate the benefit of adding an antiandrogen to surgical orchiectomy or its continued use with a GnRH analogue (combined androgen blockade (CAB)). Adding antiandrogens to orchiectomy showed no benefit, while a small benefit was shown with adding antiandrogens to GnRH analogues.[citation needed]

Unfortunately, therapies which lower testosterone levels, such as orchiectomy or GnRH analogue administration, also have significant side effects. Compared to these therapies, treatment with antiandrogens exhibits "fewer hot flashes, less of an effect on libido, less muscle wasting, fewer personality changes, and less bone loss." However, antiandrogen therapy alone is less effective than surgery. Nevertheless, given the advanced age of many with prostate cancer, as well as other features, many men may choose antiandrogen therapy alone for a better quality of life.[7]

Off-label uses[edit]

Flutamide is sometimes used as a component of hormone replacement therapy for trans women. However, its use for this purpose is discouraged due to reports of hepatotoxicity in prostate cancer patients at comparable doses (albeit very rarely – 3 in every 10,000, or 0.0003%[8]).[9] Nilutamide, another non-steroidal antiandrogen, has also been used for this indication, but its use in general has, similarly to flutamide, been discouraged (due to its unique risk of interstitial pneumonitis as well as other unique adverse effects).[10][11] Bicalutamide is now regarded as the preferred choice of a non-steroidal antiandrogen relative to flutamide and nilutamide due namely to its much better safety profile.[3]

Side effects[edit]

In addition to the effects previously mentioned, flutamide may also induce gynecomastia. Tamoxifen can partially counteract this effect. Some patients experience mild liver injury, which resolves when the drug is discontinued. It may also cause gastrointestinal side effects; one reason bicalutamide is replacing flutamide is that it appears to exhibit these to a lesser degree.

Pharmacology[edit]

Flutamide acts as a silent antagonist of the androgen receptor.

Flutamide, unlike bicalutamide,[12] crosses the blood-brain-barrier.[13]

Pharmacokinetics[edit]

After absorption, flutamide is quickly α-hydroxylated to its primary active form, hydroxyflutamide. It is excreted in various forms in the urine, the primary form being 2-amino-5-nitro-4-(trifluoromethyl)phenol.

Flutamide has a fairly short half-life of 5-6 hours,[3] and as a result, must be administered three times daily (every 8 hours). In contrast, the newer non-steroidal antiandrogens nilutamide and bicalutamide have half-lives of approximately 2 days and 6 days, respectively,[11] which allow for once-daily administration in their cases.[14]

Chemistry[edit]

Unlike the hormones with which it competes, flutamide is not a steroid; rather, it is a substituted anilide. Hence, it is frequently described as non-steroidal in order to distinguish it from older steroidal antiandrogens such as cyproterone acetate and megestrol acetate.

Synthesis[edit]

See also[edit]

Notes[edit]

  1. ^ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 573–. ISBN 978-1-4757-2085-3. 
  2. ^ "Polycystic Ovary Syndrome - Treatment - NHS Choices". Nhs.uk. 2011-10-17. Retrieved 2013-01-04. 
  3. ^ a b c James Leonard Gulley (2011). Prostate Cancer. Demos Medical Publishing. pp. 81–. ISBN 978-1-935281-91-7. 
  4. ^ Lutz Moser (1 January 2008). Controversies in the Treatment of Prostate Cancer. Karger Medical and Scientific Publishers. pp. 41–42. ISBN 978-3-8055-8524-8. 
  5. ^ David E. Neal (1994). Tumours in Urology. Springer Science & Business Media. pp. 233–. ISBN 978-1-4471-2086-5. 
  6. ^ Vera Regitz-Zagrosek (2 October 2012). Sex and Gender Differences in Pharmacology. Springer Science & Business Media. pp. 575–. ISBN 978-3-642-30725-6. 
  7. ^ Scher, Howard I. (2005). "Hyperplastic and Malignant Diseases of the Prostate". In Dennis L. Kasper, Anthony S. Fauci, Dan L. Longo, Eugene Braunwald, Stephen L. Hauser, & J. Larry Jameson (Eds.), Harrison's Principles of Internal Medicine (16th edition), pp. 548–9. New York: McGraw-Hill.
  8. ^ J. Ramon; L.J. Denis (5 June 2007). Prostate Cancer. Springer Science & Business Media. pp. 256–. ISBN 978-3-540-40901-4. 
  9. ^ Dahl, M., Feldman, J., Goldberg, J.M., Jaberi, A., Bockting, W.O., and Knudson, G. (2006). Endocrine therapy for transgender adults in British Columbia: Suggested guidelines. Vancouver, BC: Vancouver Health Authority.
  10. ^ Chawnshang Chang (1 January 2005). Prostate Cancer: Basic Mechanisms and Therapeutic Approaches. World Scientific. pp. 10–. ISBN 978-981-256-920-2. 
  11. ^ a b Louis J Denis; Keith Griffiths; Amir V Kaisary; Gerald P Murphy (1 March 1999). Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment. CRC Press. pp. 280–. ISBN 978-1-85317-422-3. 
  12. ^ Furr BJ, Tucker H (1996). "The preclinical development of bicalutamide: pharmacodynamics and mechanism of action". Urology 47 (1A Suppl): 13–25; discussion 29–32. doi:10.1016/S0090-4295(96)80003-3. PMID 8560673. 
  13. ^ Hormones - Antineoplastics: Advances in Research and Application: 2011 Edition: ScholarlyPaper. ScholarlyEditions. 9 January 2012. pp. 9–. ISBN 978-1-4649-4785-8. 
  14. ^ Alan J. Wein; Louis R. Kavoussi; Andrew C. Novick; Alan W. Partin; Craig A. Peters (25 August 2011). Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. pp. 2939–. ISBN 978-1-4160-6911-9. 
  15. ^ Stabile, R. G.; Dicks, A. P. (2003). "Microscale Synthesis and Spectroscopic Analysis of Flutamide, an Antiandrogen Prostate Cancer Drug". Journal of Chemical Education 80 (12): 1439. doi:10.1021/ed080p1439.  edit
  16. ^ Baker, J. W.; Bachman, G. L.; Schumacher, I.; Roman, D. P.; Tharp, A. L. (1967). "Synthesis and Bacteriostatic Activity of Some Nitrotrifluoro methylanilides". Journal of Medicinal Chemistry 10 (1): 93–5. doi:10.1021/jm00313a020. PMID 6031711.  edit
  17. ^ Bandgar, B. P.; Sawant, S. S. (2006). "Novel and Gram‐Scale Green Synthesis of Flutamide". Synthetic Communications 36 (7): 859. doi:10.1080/00397910500464848.  edit

References[edit]

  1. Chrousos, George P; Zoumakis, Emmanouil; & Gravanis, Achille. (2001). In Bertram G. Katzung (Ed.), Basic and Clinical Pharmacology (8th edition), pp 704–7. New York: Lange Medical Books/McGraw-Hill.
  2. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3397. PubChem. Accessed on December 3, 2005.
  3. http://www.rxlist.com/cgi/generic2/flutam_cp.htm. RxList. Accessed on December 3, 2005.

External links[edit]