Flutamide
Encyclopedia
Flutamide is an oral nonsteroidal antiandrogen
drug
primarily used to treat prostate cancer
. It competes with testosterone
and its powerful metabolite
, dihydrotestosterone
(DHT) for binding to androgen receptor
s in the prostate gland. By doing so, it prevents them from stimulating the prostate cancer cells to grow. Flutamide has been largely replaced by a newer member of this class, bicalutamide
, due to a better side-effect
profile. Flutamide may also be used to treat excess androgen levels in women - especially those with PolyCystic Ovarian Syndrom (PCOS).http://www.nhs.uk/Conditions/Polycystic-ovarian-syndrome/Pages/Treatment.aspx It is marketed by Schering-Plough
under the brand name Eulexin. It is also known as Flutamin.
; rather, it is a substituted anilide. After absorption, the molecule is quickly α-hydroxylated to its primary active form, hydroxyflutamide. Flutamide is excreted in various forms in the urine
, the primary form being 2-amino-5-nitro-4-(trifluoromethyl) phenol.
(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 androgen
s can provide powerful treatment for prostate cancer, especially metastatic disease. Normally administered are analogue
s 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 anti-androgens 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.
. 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.
Antiandrogen
Antiandrogens, or androgen antagonists, first discovered in the 1960s, prevent androgens from expressing their biological effects on responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell's surface, or affecting...
drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
primarily used to treat prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
. It competes with testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
and its powerful metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
, dihydrotestosterone
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
(DHT) for binding to androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
s in the prostate gland. By doing so, it prevents them from stimulating the prostate cancer cells to grow. Flutamide has been largely replaced by a newer member of this class, bicalutamide
Bicalutamide
Bicalutamide is an oral non-steroidal anti-androgen used in the treatment of prostate cancer and hirsutism...
, due to a better side-effect
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
profile. Flutamide may also be used to treat excess androgen levels in women - especially those with PolyCystic Ovarian Syndrom (PCOS).http://www.nhs.uk/Conditions/Polycystic-ovarian-syndrome/Pages/Treatment.aspx It is marketed by Schering-Plough
Schering-Plough
Schering-Plough Corporation was a United States-based pharmaceutical company. It was founded in 1851 by Ernst Christian Friedrich Schering as Schering AG in Germany. In 1971, the Schering Corporation merged with Plough to form Schering-Plough. On November 4, 2009 Merck & Co...
under the brand name Eulexin. It is also known as Flutamin.
Structure
Unlike the hormones with which it competes, flutamide is not a steroidSteroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
; rather, it is a substituted anilide. After absorption, the molecule is quickly α-hydroxylated to its primary active form, hydroxyflutamide. Flutamide is excreted in various forms in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, the primary form being 2-amino-5-nitro-4-(trifluoromethyl) phenol.
Use in prostate cancer
Gonadotropin-releasing hormoneGonadotropin-releasing hormone
Gonadotropin-releasing hormone , also known as Luteinizing-hormone-releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. GnRH is synthesized and released from neurons within...
(GnRH) is released by the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
in a pulsatile fashion; this causes the anterior
Anterior pituitary
A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland...
pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
to release luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
(LH) and follicle-stimulating hormone
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
(FSH). LH stimulates the testes to produce testosterone, which is metabolized to DHT by the enzyme 5α-reductase
5-alpha reductase
5α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism, and prostate cancer....
.
DHT, and to a much smaller extent, testosterone, stimulate prostate cancer cells to grow. Therefore, blocking these androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s can provide powerful treatment for prostate cancer, especially metastatic disease. Normally administered are analogue
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
s of GnRH, such as leuprolide
Leuprolide
Leuprorelin or leuprolide acetate is a GnRH analog. Proper Sequence: Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt - Mode of action:Leuprolide acts as an agonist at pituitary GnRH receptors...
or goserelin
Goserelin
Goserelin acetate is an injectable gonadotropin releasing hormone superagonist , also known as a luteinizing hormone releasing hormone agonist. Structurally, it is a decapeptide...
. 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 anti-androgens 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.
Side effects
In addition to the effects previously mentioned, flutamide may also induce gynecomastiaGynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
. Tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
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.
External links
- Schering-Plough (manufacturer's website)