elevated >5 times the normal upper limit. sources: gynecomastia flutamide, as a monotherapy, causes gynecomastia in 30 to 79% of men, and also produces breast tenderness. however, more than 90% of cases of gynecomastia with nsaas including flutamide are mild to moderate. tamoxifen, a selective estrogen receptor modulator (serm) with predominantly antiestrogenic actions, can counteract flutamide-induced gynecomastia and breast pain in men. diarrhea diarrhea is more common and sometimes more severe with flutamide than with other nsaas. in a comparative trial of combined androgen blockade for prostate cancer, the rate of diarrhea was 26% for flutamide and 12% for bicalutamide. moreover, 6% of flutamide-treated patients discontinued the medication due to diarrhea, whereas only 0.5% of bicalutamide-treated patients did so. in the case of antiandrogen monotherapy for prostate cancer, the rates of diarrhea are 5 to 20% for flutamide, 2 to 5% for bicalutamide, and 2 to 4% for nilutamide. in contrast to diarrhea, the rates of nausea and vomiting are similar among the three medications. liver toxicity although rare, flutamide has been associated with severe hepatotoxicity and death. by 1996, 46 cases of severe cholestatic hepatitis had been reported, with 20 fatalities. there have been continued case reports since, including liver transplants and death. a 2021 review of the literature found 15 cases of serious hepatotoxicity in women treated with flutamide, including 7 liver transplantations and 2 deaths. based on the number of prescriptions written and the number of cases reported in the medwatch database, the rate of serious hepatotoxicity associated with flutamide treatment was estimated in 1996 as approximately 0.03% (3 per 10,000). however, other research has suggested that the true incidence of significant hepatotoxicity with flutamide may be much greater, as high as 0.18 to 10%. flutamide is also associated with liver enzyme elevations in up to 42 to 62% of patients, although marked elevations in liver enzymes (above 5 times upper normal limit) occur only in 3 to 5%. the risk of hepatotoxicity with flutamide is much higher than with nilutamide or bicalutamide. lower doses of the medication appear to have a possibly reduced but still significant risk. liver function should be monitored regularly with liver function tests during flutamide treatment. in addition, due to the high risk of serious hepatotoxicity, flutamide should not be used in the absence of a serious indication. the mechanism of action of flutamide-induced hepatotoxicity is thought to be due to mitochondrial toxicity. specifically, flutamide and particularly its major metabolite hydroxyflutamide inhibit enzymes in the mitochondrial electron transport chain in hepatocytes, including respiratory complexes i (nadh ubiquinone oxidoreductase), ii (succinate dehydrogenase), and v (atp synthase), and thereby reduce cellular respiration via atp depletion and hence decrease cell survival. inhibition of taurocholate (a bile acid) efflux has also been implicated in flutamide-induced hepatotoxicity. in contrast to flutamide and hydroxyflutamide, which severely compromise hepatocyte cellular respiration in vitro, bicalutamide does not significantly do so at the same concentrations and is regarded as non-mitotoxic. it is thought that the nitroaromatic group of flutamide and hydroxyflutamide enhance their mitochondrial toxicity; bicalutamide, in contrast, possesses a cyano group in place of the nitro moiety, greatly reducing the potential for such toxicity. the hepatotoxicity of flutamide appears to depend on hydrolysis of flutamide catalyzed by an arylacetamide deacetalyse enzyme. this is analogous to the hepatotoxicity that occurs with the withdrawn paracetamol (acetominophen)-related medication phenacetin. in accordance, the combination of paracetamol (acetaminophen) and flutamide appears to result in additive to synergistic hepatotoxicity, indicating a potential drug interaction. hepatotoxicity with flutamide may be cross-reactive with that of cyproterone acetate. others flutamide has also been associated with interstitial pneumonitis (which can progress to pulmonary fibrosis). the incidence of interstitial pneumonitis with flutamide was found to be 0.04% (4 per 10,000) in a large clinical cohort of 41,700 prostate cancer patients. a variety of case reports have associated flutamide with photosensitivity. flutamide has been associated with several case reports of methemoglobinemia. bicalutamide does not appear to share this risk with flutamide. flutamide has also been associated with reports of sulfhemoglobinemia and neutropenia. birth defects out of the available endocrine-disrupting compounds looked at, flutamide has a notable effect on anogenital distance in rats.) pharmacology pharmacodynamics hydroxyflutamide, the active form of flutamide. antiandrogenic activity affinities compound rba metribolone 100 dihydrotestosterone 85 cyproterone acetate 7.8 bicalutamide 1.4 nilutamide 0.9 hydroxyflutamide 0.57 flutamide <0.0057 notes: at androgen receptors; measured in human prostate tissue. relative to metribolone, which is by definition 100% relative potencies of selected antiandrogens antiandrogenrelative potency bicalutamide4.3 hydroxyflutamide3.5 flutamide3.3 cyproterone acetate1.0 zanoterone0.4 description: relative potencies of orally administered antiandrogens in antagonizing 0.8 to 1.0 mg/kg s.c. testosterone propionate-induced ventral prostate weight increase in castrated immature male rats. higher values mean greater potency. sources: see template. androgen receptor antagonistic potency of spironolactone, cyproterone acetate, and flutamide in castrated male rats treated with exogenous testosterone (as measured by inhibition of androgen-dependent ventral prostate weight). bicalutamide is a much more potent androgen receptor antagonist than flutamide both in animals and in humans. flutamide 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 flutamide, and hence is a much more potent ar antagonist in comparison. however, at high concentrations, unlike flutamide, hydroxyflutamide is able to weakly activate the ar. flutamide 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 flutamide is used appear to compensate for this. in accordance with its selectivity for the ar, flutamide 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 flutamide 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, flutamide crosses the blood–brain barrier and exerts central antiandrogen actions. flutamide 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 flutamide (a 15-fold difference), circulating levels of flutamide at steady-state have been found to be approximately 7.5-fold lower than those of bicalutamide. moreover, whereas flutamide 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 flutamide in a large clinical trial for prostate cancer. also, bicalutamide has been shown to be 5-fold more potent than flutamide in rats and 50-fold more potent than flutamide in dogs. taken together, flutamide appears to be a considerably less potent and efficacious antiandrogen than is bicalutamide. dose-ranging studies of flutamide in men with benign prostatic hyperplasia and prostate cancer alone and in combination with a gnrh agonist have been performed. flutamide increases testosterone levels by 5- to 10-fold in gonadally intact male rats. relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor speciesic50 (nm)rba (ratio) bicalutamide2-hydroxyflutamidenilutamidebica / 2-oh-flubica / niluref rat190700nd4.0nd rat~400~900~9002.32.3 ratndndnd3.3nd rata35954565186201.35.2 human~300~700~5002.51.6 human~100~300nd~3.0nd humana2490234553001.02.1 footnotes: a = controversial data. sources: see template. plasma levels and binding potential of flutamide and bicalutamide during first week daytotal levels (ng/ml)free levels (ng/ml)ratios bicalutamideflutamideabicalutamideflutamideafreebinding potentialb 190194036.0660.552.18 21613150064.51050.612.46 32345150093.81050.893.57 429691500118.81051.134.53 742591500170.41051.626.49 notes: during first week of treatment. dosages not provided. footnotes: a = as 2-hydroxyflutamide (the active form of flutamide). b = assumes, on the basis of ligand binding assays, that bicalutamide possesses 4-fold greater affinity for the androgen receptor than 2-hydroxyflutamide. sources: see template. cyp17a1 inhibition flutamide 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, flutamide has been found to slightly but significantly lower androgen levels in gnrh analogue-treated male prostate cancer patients and women with polycystic ovary syndrome. in a directly comparative study of flutamide monotherapy (375 mg once daily) versus bicalutamide monotherapy (80 mg once daily) in japanese men with prostate cancer, after 24 weeks of treatment flutamide decreased dehydroepiandrosterone (dhea) levels by about 44% while bicalutamide increased them by about 4%. as such, flutamide is a weak inhibitor of androgen biosynthesis. however, the clinical significance of this action may be limited when flutamide 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 flutamide has been identified as an agonist of the aryl hydrocarbon receptor. this may be involved in the hepatotoxicity of flutamide. pharmacokinetics the absorption of flutamide is complete upon oral ingestion. food has no effect on the bioavailability of flutamide. steady-state levels of hydroxyflutamide, the active form of flutamide, are achieved after 2 to 4 days administration. levels of hydroxyflutamide are approximately 50-fold higher than those of flutamide at steady-state. the plasma protein binding of flutamide and hydroxyflutamide are high; 94 to 96% and 92 to 94%, respectively. flutamide and its metabolite hydroxyflutamide are known to be transported by the multidrug resistance-associated protein 1 (mrp1; abcc1). flutamide 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 flutamide one hour post-ingestion), and to at least five other, minor metabolites. flutamide has at least 10 inactive metabolites total, including 4-nitro-3-fluoro-methylaniline. flutamide is excreted in various forms in the urine, the primary form being 2-amino-5-nitro-4-(trifluoromethyl)phenol. flutamide 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 flutamide and hydroxyflutamide are regarded as too short to allow for once-daily dosing, and for this reason, flutamide 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. chemistry unlike the hormones with which it competes, flutamide is not a steroid; rather, it is a substituted anilide. hence, it is described as nonsteroidal in order to distinguish it from older steroidal antiandrogens such as cyproterone acetate and megestrol acetate. synthesis synthesis. patents: schotten–baumann reaction between 4-nitro-3-(trifluoromethyl)aniline (1) with isobutanoyl chloride (2) in the presence of triethylamine. history flutamide was first synthesized in 1967 by neri and colleagues at schering plough corporation. it was originally synthesized as a bacteriostatic agent, but was subsequently, and serendipitously found to possess antiandrogen activity. the code name of flutamide during development was sch-13521. clinical research of the medication began in 1971, and it was first marketed in 1983, specifically in chile under the brand name drogenil and in west germany under the brand name flugerel. flutamide was not introduced in the united states until 1989; it was specifically approved by the u.s. food and drug administration for the treatment of metastatic prostate cancer in combination with a gonadotropin-releasing hormone (gnrh) analogue. the medication was first studied for the treatment of hirsutism in women in 1989. it was the first "pure antiandrogen" to be studied in the treatment of hirsutism. flutamide was the first nsaa to be introduced, and was followed by nilutamide in 1989 and then bicalutamide in 1995. society and culture generic names flutamide is the generic name of the drug and its inn, usan, ban, dcf, and jan. its names in