Pharmacodynamics Hydroxyflutamide, the active form of<unk> . Antiandrogenic activity<unk>  acts as a selective, competitive, silent antagonist of the androgen receptor (AR). Its active form, hydroxyflutamide, has between 10- to 25-fold higher affinity for the AR than does<unk> , and hence is a much more potent AR antagonist in comparison. However, at high concentrations, unlike<unk> , hydroxyflutamide is able to weakly activate the AR.<unk>  has far lower affinity for the AR than do steroidal antiandrogens like spironolactone and cyproterone acetate, and it is a relatively weak antiandrogen in terms of potency by weight, but the large dosages at which<unk>  is used appear to compensate for this. In accordance with its selectivity for the AR,<unk>  does not interact with the progesterone, estrogen, glucocorticoid, or mineralocorticoid receptor, and possesses no intrinsic progestogenic, estrogenic, glucocorticoid, or antigonadotropic activity. However, it can have some indirect estrogenic effects via increased levels of estradiol secondary to AR blockade, and this involved in the gynecomastia it can produce. Because<unk>  does not have any estrogenic, progestogenic, or antigonadotropic activity, the medication does not cause menstrual irregularities in women. This is in contrast to steroidal antiandrogens like spironolactone and cyproterone acetate. Similarly to nilutamide, bicalutamide, and enzalutamide,<unk>  crosses the blood–brain barrier and exerts central antiandrogen actions.<unk>  has been found to be equal to slightly more potent than cyproterone acetate and substantially more potent than spironolactone as an antiandrogen in bioassays. This is in spite of the fact that hydroxyflutamide has on the order of 10-fold lower affinity for the AR relative to cyproterone acetate. Hydroxyflutamide shows about 2- to 4-fold lower affinity for the rat and human AR than does bicalutamide. In addition, whereas bicalutamide has an elimination half-life of around 6 days, hydroxyflutamide has an elimination half-life of only 8 to 10 hours, a roughly 17-fold difference. In accordance, at dosages of 50 mg/day bicalutamide and 750 mg/day<unk>  (a 15-fold difference), circulating levels of<unk>  at steady-state have been found to be approximately 7.5-fold lower than those of bicalutamide. Moreover, whereas<unk>  at this dosage has been found to produce a 75% reduction in prostate-specific antigen levels in men with prostate cancer, a fall of 90% has been demonstrated with this dosage of bicalutamide. In accordance, 50 mg/day bicalutamide has been found to possess equivalent or superior effectiveness to 750 mg/day<unk>  in a large clinical trial for prostate cancer. Also, bicalutamide has been shown to be 5-fold more potent than<unk>  in rats and 50-fold more potent than<unk>  in dogs. Taken together,<unk>  appears to be a considerably less potent and efficacious antiandrogen than is bicalutamide. Dose-ranging studies of<unk>  in men with benign prostatic hyperplasia and prostate cancer alone and in combination with a GnRH agonist have been performed.<unk>  increases testosterone levels by 5- to 10-fold in gonadally intact male rats. CYP17A1 inhibition<unk>  and hydroxyflutamide have been found in vitro to inhibit CYP17A1 (17α-hydroxylase/17,20-lyase), an enzyme which is required for the biosynthesis of androgens. In accordance,<unk>  has been found to slightly but significantly lower androgen levels in GnRH analogue-treated male prostate cancer patients and women with polycystic ovary syndrome. As such,<unk>  is a weak inhibitor of androgen biosynthesis. However, the clinical significance of this action may be limited when<unk>  is given without a GnRH analogue to non-castrated men, as the medication markedly elevates testosterone levels into the high normal male range via prevention of AR activation-mediated negative feedback on the hypothalamic–pituitary–gonadal axis in this context. Other activities<unk>  has been identified as an agonist of the aryl hydrocarbon receptor. This may be involved in or responsible for the hepatotoxicity of<unk> . Pharmacokinetics The absorption of<unk>  is complete upon oral ingestion. Food has no effect on the bioavailability of<unk> . Steady-state levels of hydroxyflutamide, the active form of<unk> , are achieved after 2 to 4 days administration. Levels of hydroxyflutamide are approximately 50-fold higher than those of<unk>  at steady-state. The plasma protein binding of<unk>  and hydroxyflutamide are high; 94 to 96% and 92 to 94%, respectively.<unk>  is metabolized by CYP1A2 (via α-hydroxylation) in the liver during first-pass metabolism to its main metabolite hydroxyflutamide (which accounts for 23% of an oral dose of<unk>  one hour post-ingestion), and to at least five other, minor metabolites.<unk>  has at least 10 inactive metabolites total, including 4-nitro-3-fluoro-methylaniline.<unk>  is excreted in various forms in the urine, the primary form being 2-amino-5-nitro-4-(trifluoromethyl)phenol.<unk>  and hydroxyflutamide have elimination half-lives of 4.7 hours and 6 hours in adults, respectively. However, the half-life of hydroxyflutamide is extended to 8 hours after a single dose and to 9.6 hours at steady state) in elderly individuals. The elimination half-lives of<unk>  and hydroxyflutamide are regarded as too short to allow for once-daily dosing, and for this reason,<unk>  is instead administered three times daily at 8-hour intervals. In contrast, the newer NSAAs nilutamide, bicalutamide, and enzalutamide all have much longer half-lives, and this allows for once-daily administration in their cases.
Flutamide
Darolutamide
Bicalutamide
Nilutamide
Topilutamide
Apalutamide
Acetothiolutamide
Enzalutamide