Flutamide

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Flutamide
File:Flutamide structural formulae.png
File: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 Number 13311-84-7 YesY
ATC code L02BB01 (WHO)
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
  • O=C(Nc1cc(c(cc1)[N+]([O-])=O)C(F)(F)F)C(C)C
  • InChI=1S/C11H11F3N2O3/c1-6(2)10(17)15-7-3-4-9(16(18)19)8(5-7)11(12,13)14/h3-6H,1-2H3,(H,15,17) YesY
  • Key:MKXKFYHWDHIYRV-UHFFFAOYSA-N YesY
  (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

Prostate cancer

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

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 0.03 %[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

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

Flutamide acts as a silent antagonist of the androgen receptor.

Flutamide crosses the blood-brain-barrier.[12]

Pharmacokinetics

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.[13]

Chemistry

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

File:Flutamide synthesis.png
Flutamide synthesis:[14][15][16] Schering, DE 2130450  DE 2261293  U.S. Patent 3,847,988 U.S. Patent 4,144,270

See also

Notes

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References

  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

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  3. ↑ 3.0 3.1 3.2 Lua error in package.lua at line 80: module 'strict' not found.
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  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. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  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. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ 11.0 11.1 Lua error in package.lua at line 80: module 'strict' not found.
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  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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