|Systematic (IUPAC) name|
|Protein binding||94 to 96%|
|Excretion||>90% via urine|
|Molar mass||276.212 g/mol|
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. 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. Flutamide has been largely replaced by newer non-steroidal antiandrogens, namely bicalutamide, due to better safety, tolerability, and pharmacokinetic profiles.
Flutamide was first introduced into clinical use in 1975, 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.
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.
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.
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.
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 %). 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). 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.
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.
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, 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, which allow for once-daily administration in their cases.
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.
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