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 cat.
  • D
Legal status
  • Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability >90%
Protein binding 94 to 96%
Excretion >90% via urine
Identifiers
CAS number 13311-84-7 YesY
ATC code L02BB01
PubChem CID 3397
DrugBank DB00499
ChemSpider 3280 YesY
UNII 76W6J0943E YesY
KEGG D00586 YesY
ChEBI CHEBI:5132 YesY
ChEMBL CHEMBL806 YesY
Chemical data
Formula C11H11F3N2O3 
Mol. mass 276.212 g/mol
 YesY (what is this?)  (verify)

Flutamide (brand names Eulexin, Flutamin, Cytomid) is an oral, non-steroidal antiandrogen drug primarily used to treat prostate cancer. It acts as a silent antagonist of the androgen receptor (AR), competing with testosterone and its powerful 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. Flutamide has been largely replaced by newer members of this class, such as bicalutamide, due to better side effect profiles. In addition to its use in prostate cancer, flutamide may also be used to treat excess androgen levels in women, especially in those with polycystic ovary syndrome.[1]

Use[edit]

Prostate cancer[edit]

Gonadotropin-releasing hormone (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 much 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 analogues of GnRH, such as leuprolide or goserelin. Although they stimulate the same receptors that GnRH does, since they are present continuously and not in a pulsatile manner, they serve to inhibit the pituitary 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-analogue therapy to block this surge, and it and other nonsteroidal antiandrogens continue in this use.

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

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.[2]

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 the reports of hepatotoxicity in prostate cancer patients at comparable doses.[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.

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 duration, and as a result, must be administered three times daily (every 8 hours).

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.

Synthesis[edit]

Flutamide synthesis:[4][5][6] Rudolph O. Neri, John G. Topliss; Schering Corporation, U.S. Patent 4,144,270 (1979).

See also[edit]

Notes[edit]

  1. ^ "Polycystic Ovary Syndrome - Treatment - NHS Choices". Nhs.uk. 2011-10-17. Retrieved 2013-01-04. 
  2. ^ 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.
  3. ^ 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.
  4. ^ 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
  5. ^ 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
  6. ^ 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]