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Flutamide (also known as SCH13521; SCH-13521; trade names: Flucinom; Flugerel; Niftolid; Flutan; Oncosal etc.), a toluidine derivative, is a potent non-steroidal antiandrogen drug (AR antagonist) with potential anticancer activity. It is mainly used for the treatment of prostate cancer. Flutamide can be transformed into an active metablolite that binds to androgen receptor with a Ki value of 55 nM. Flutamideis a toluidine derivative and nonsteroidal antiandrogen that is structurally related to bicalutamide and nilutamide. Flutamide and the more active metabolite 2-hydroxyflutamide competitively block dihydrotestosterone binding at androgen receptors, forming inactive complexes which cannot translocate into the cell nucleus.
Physicochemical Properties
| Molecular Formula | C11H11F3N2O3 |
| Molecular Weight | 276.21 |
| Exact Mass | 276.072 |
| CAS # | 13311-84-7 |
| Related CAS # | Flutamide-d7;223134-72-3 |
| PubChem CID | 3397 |
| Appearance | Light yellow to yellow solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 400.3±45.0 °C at 760 mmHg |
| Melting Point | 112 °C |
| Flash Point | 195.9±28.7 °C |
| Vapour Pressure | 0.0±0.9 mmHg at 25°C |
| Index of Refraction | 1.521 |
| LogP | 3.72 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 2 |
| Heavy Atom Count | 19 |
| Complexity | 352 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | MKXKFYHWDHIYRV-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C11H11F3N2O3/c1-6(2)10(17)15-7-3-4-9(16(18)19)8(5-7)11(12,13)14/h3-6H,1-2H3,(H,15,17) |
| Chemical Name | N-(4-nitro-3-(trifluoromethyl)phenyl)isobutyramide |
| Synonyms | SCH-13521; SCH13521; SCH 13521; trade names: Flucinom; Flugerel; Niftolid; Flutan; Oncosal; Profamid; Prostacur; Flutaplex; Fugerel; Grisetin; Eulexin; Apimid; Chimax; Drogenil; Euflex; Eulexine; Flucinome; Fluken; Flulem; Flutabene; Flutacan; FlutaGry; Flutamex; Flutamin; Prostadirex; Prostica; Prostogenat; Tafenil; Tecnoflut; Testotard. FLUT. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | Flutamide-OH is the active metabolite of flutamide. Rat anterior pituitary androgen receptor (Ki=55 nM) is directly bonded to both of them[1]. Flutamide solely exhibits antiandrogenic effects rather than androgenic effects when it comes to the growth of an androgen-sensitive clone of mouse mammary cancer Shionogi SC -l 15 cells in culture[2]. When used with leuprolide, flutamide treats prostate cancer[3]. PC3 and LNCap are both susceptible to the cytotoxic effects of flutamide (IC50s of 20 μM and 12 μM, respectively). In PC3 and LNCap cells, flutamide (10 μM, 5 μM; 48 h) causes apoptosis and inhibits cell migration and colonization[4]. Moreover, flutamide inhibits the expression of the genes involved in the EMT pathway and KLK2 in cells[4]. | ||
| ln Vivo | Rat ventral prostate weight decreases significantly with flutamide, from 319 mg to 245 mg. When flutamide and an LHRH agonist are combined, there is an additive effect that results in a reduction in prostatic ODC activity and a drop in prostate weight to 101 mg[5]. In heat-stressed mice, flutamide (12.5–50 mg/kg; sc; once daily for three days) reduces the symptoms of heat stroke[6]. | ||
| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Rapidly and completely absorbed. Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of a single dose excreted in the feces over 72 hours. Metabolism / Metabolites Flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. Flutamide has known human metabolites that include 2-hydroxy-flutamide. Flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. Route of Elimination: Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of a single dose excreted in the feces over 72 hours. Half Life: The plasma half-life for the alpha-hydroxylated metabolite of flutamide (an active metabolite) is approximately 6 hours. Biological Half-Life The plasma half-life for the alpha-hydroxylated metabolite of flutamide (an active metabolite) is approximately 6 hours. |
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| Toxicity/Toxicokinetics |
Hepatotoxicity Chronic therapy with flutamide is associated with elevations in serum aminotransferase levels in up to 62% of patients, but marked elevations (above 5 times ULN) in only 3% to 5%. Most of these abnormalities are transient, asymptomatic and do not require dose adjustment or drug discontinuation. However, in 0.1% to 1% of patients, acute liver injury with symptoms and jaundice arises which can be prolonged, severe and even fatal. The latency of onset ranges widely from 1 to 10 months (Cases 2 and 3), averaging 3 months. Allergic manifestations are rare as are autoantibodies. The pattern of liver enzyme elevations is most commonly hepatocellular, but many cases with cholestatic and mixed patterns have been described. Liver failure with a requirement for emergency liver transplantation or fatality has been described in many publications with 20 fatal cases reported from the FDA MedWatch program during the first 5 years of its availability. Fatal cases have been reported in children and young women being treated for hirsutism or acne (Case 1). Current recommendations for routine monitoring of liver tests include ALT levels monthly for the first 4 months of flutamide therapy and regularly thereafter with prompt discontinuation if ALT levels rise above twice ULN. Nevertheless, well characterized fatal cases have occurred despite such monitoring, the onset of injury being abrupt and injury continuing for several weeks after discontinuation of flutamide. The injury may be partially dose related as long term use of lower doses of flutamide (62.5 and 125 mg/day) has not been associated with high rates of ALT elevations or clinically apparent liver injury. Likelihood score: A (well known cause of clinically apparent liver injury). Protein Binding 94-96% |
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| References |
[1]. Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Mol Cell Endocrinol. 1986 Mar;44(3):261-70. [2]. Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture. J Steroid Biochem. 1988 Nov;31(5):845-52. [3]. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989 Aug 17;321(7):419-24. [4]. The effect of Ganoderma lucidum polysaccharide extract on sensitizing prostate cancer cells to flutamide and docetaxel: an in vitro study. Sci Rep. 2023 Nov 2;13(1):18940. [5]. Flutamide, an androgen receptor antagonist, improves heatstroke outcomes in mice. Eur J Pharmacol. 2012 Aug 5;688(1-3):62-7. [6]. Characteristics of flutamide action on prostatic and testicular functions in the rat. J Steroid Biochem. 1988 Jun;29(6):691-8. |
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| Additional Infomation |
Flutamide can cause developmental toxicity according to state or federal government labeling requirements. Flutamide is a monocarboxylic acid amide and a member of (trifluoromethyl)benzenes. It has a role as an androgen antagonist and an antineoplastic agent. An antiandrogen with about the same potency as cyproterone in rodent and canine species. Flutamide is an Androgen Receptor Inhibitor. The mechanism of action of flutamide is as an Androgen Receptor Antagonist. Flutamide is a first generation, oral nonsteroidal antiandrogen that has been used widely in the therapy of prostate cancer. Flutamide is frequently associated with minor serum aminotransferase elevations and has been linked to numerous cases of acute liver injury, which are frequently severe and can be fatal. Flutamide is a toluidine derivative and a nonsteroidal antiandrogen that is structurally related to bicalutamide and nilutamide. Flutamide and its more potent active metabolite 2-hydroxyflutamide competitively block dihydrotestosterone binding at androgen receptors, forming inactive complexes which cannot translocate into the cell nucleus. Formation of inactive receptors inhibits androgen-dependent DNA and protein synthesis, resulting in tumor cell growth arrest or transient tumor regression. (NCI04) An antiandrogen with about the same potency as cyproterone in rodent and canine species. An antiandrogen with about the same potency as cyproterone in rodent and canine species. Drug Indication For the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate FDA Label Mechanism of Action Flutamide is a nonsteroidal antiandrogen that blocks the action of both endogenous and exogenous testosterone by binding to the androgen receptor. In addition Flutamide is a potent inhibitor of testosterone-stimulated prostatic DNA synthesis. Moreover, it is capable of inhibiting prostatic nuclear uptake of androgen. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.05 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (9.05 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (9.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.6204 mL | 18.1022 mL | 36.2043 mL | |
| 5 mM | 0.7241 mL | 3.6204 mL | 7.2409 mL | |
| 10 mM | 0.3620 mL | 1.8102 mL | 3.6204 mL |