Androgen receptor (AR). Nilutamide is a nonsteroidal, silent antiandrogen that binds to the androgen receptor and prevents its activation by androgens, thereby inhibiting androgen-dependent growth of normal and neoplastic prostate cells.

In human hepatic venous bodies, nilutamide (110 μM) inhibits the enzymes hexabarbitic cardiovascular demethylase, amphetamine N-demethylase, benzo(a)pyrene venase, and 7-ethylaniline coumarin, in that order. 85%, 40%, 35%, and 25% of the protein O-determinase activity is reported[2]. Nilumid (550 μM) does not modify the kinetics of NADPH-cytochrome P-450 reductase in reducing cytochrome P-450 in NADPH anaerobic systems, nor does it significantly increase the consumption of NADPH by microparticulate oxygen [2]. In nilutamide burst T-47D cells and ZR-75-1 cells, GCDFP-15 release produced by 1 nM testosterone was dramatically elevated, with IC50 values of 87 nM and 75 nM, respectively [3].
Nilutamide binds to androgen receptors with high affinity and blocks androgen receptor activation. It also inhibits androgen biosynthesis in vitro. In rats, it inhibits androgen-induced prostate weight increase and inhibits negative androgen-dependent gonadotropin feedback, leading to an increase in luteinizing hormone and testosterone.

In rats, Nilutamide inhibits androgen-induced prostate weight increase and inhibits negative androgen-dependent gonadotropin feedback, leading to an increase in luteinizing hormone and testosterone. These effects are consistent with its antiandrogenic mechanism of action. It is used clinically for the treatment of prostate cancer.

The in vitro assay for Nilutamide's androgen receptor binding involves measuring its ability to compete with radiolabeled testosterone or dihydrotestosterone for binding to the androgen receptor. The receptor is incubated with the radioligand and varying concentrations of Nilutamide, and the amount of bound radioligand is measured. The IC50 or Ki value is determined.

Specific in vitro cell-based assay protocols for Nilutamide are not detailed. Its antiandrogenic activity can be assessed in prostate cancer cell lines, such as LNCaP cells. Cells are treated with Nilutamide in the presence of androgens, and the inhibition of androgen-dependent gene expression or cell proliferation is measured.

Animal/Disease Models: Female NMRI mice (20-22 g; n=165; infected with approximately 80 Schistosoma mansoni cercariae injected subcutaneously (sc) (sc)) [4]
Doses: 50, 100, 200 and 400 mg/kg
Route of Administration: po (po (oral gavage)) Single dose (21- or 49-day-old S. mansoni infection)
Experimental Results: Total larval load was diminished by 11.0%, 5.1%, 21.9% and 35.6% at doses of 50, 100, 200 and 400 mg/kg, respectively. Female larvae were diminished by 27.5%, 26.1%, 75.4% and 22.5% respectively at doses of 50, 100, 200 and 400 mg/kg. A moderate reduction of 30.7%-49.6% in adult worms was observed at doses of 100 and 200 mg/kg. At the dose of 400 mg/kg, the total adult worm burden and female adult worm burden were diminished by 84.8% and 71.3% respectively.
Nilutamide has been evaluated in animal models of prostate cancer, typically using xenograft models in mice. Tumor-bearing mice are treated with Nilutamide, and tumor growth inhibition is measured. These studies have supported its clinical use.

Absorption, Distribution and Excretion
Absorption is rapid and complete, resulting in high and sustained plasma concentrations. Nilumet is extensively metabolized; less than 2% of the drug is excreted unchanged in the urine after 5 days. Fecal excretion is negligible, accounting for only 1.4% to 7% of the dose after 4 to 5 days. Metabolism/Metabolites A human metabolism study using 14C radiolabeled tablets showed that nilumet is extensively metabolized; less than 2% of the drug is excreted unchanged in the urine after 5 days. Excretion Route: Nilumet is extensively metabolized; less than 2% of the drug is excreted unchanged in the urine after 5 days. Fecal excretion is minimal, accounting for only 1.4% to 7% of the dose after 4 to 5 days.
Half-life: 38.0-59.1 hours

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Biological half-life
38.0-59.1 hours
Nilutamide is orally bioavailable. It is metabolized in the liver and has a half-life of approximately 38-59 hours. It is highly protein-bound. Detailed pharmacokinetic parameters are available from clinical studies.

Toxicity Summary
Nilumet competes with androgens for androgen receptors, thereby blocking the effects of adrenal and testicular androgens that stimulate the growth of normal and malignant prostate tissue. This androgen receptor blockade may lead to growth arrest or transient tumor regression by inhibiting androgen-dependent DNA and protein synthesis. Hepatotoxicity
In large registration clinical trials, elevated ALT levels occurred in 8% (range 2% to 33%) of patients treated with nilumet. These elevations were usually mild, asymptomatic, and transient, with only 1% of patients requiring discontinuation of the drug. In rare cases, clinically apparent acute liver injury has occurred during nilumet treatment, but the number of published cases is small, and the hepatotoxicity of this drug appears to be lower than that of flutamide. Nevertheless, fatal cases have been reported (Case 1). In reported cases, the incubation period averaged 2 to 4 months, and the clinical presentation of elevated enzymes was usually hepatocellular, thus very similar to liver injury caused by flutamide. Signs of hypersensitivity and autoimmunity are uncommon.
Probability score: C (Possibly the cause of clinically obvious liver damage).
Nilutamide has side effects including visual disturbances (e.g., delayed adaptation to darkness), gastrointestinal effects, and liver toxicity. It can also cause interstitial pneumonitis. These toxicities limit its use.

[1]. Nilutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer. Drugs Aging. 1993 Jan-Feb;3(1):9-25.

[2]. Inhibitory effects of nilutamide, a new androgen receptor antagonist, on mouse and human liver cytochrome P-450. Biochem Pharmacol. 1989 Mar 15;38(6):941-7.

[3]. Comparison of in vitro effects of the pure antiandrogens OH-flutamide, Casodex, and nilutamide on androgen-sensitive parameters. Urology. 1997 Apr;49(4):580-6; discussion 586-9.

[4]. Keiser J, Vargas M, Vennerstrom JL. Activity of antiandrogens against juvenile and adult Schistosoma mansoni in mice. J Antimicrob Chemother. 2010 Sep;65(9):1991-5.

Nilumet is an imidazolidinone compound belonging to the (trifluoromethyl)benzene class and C-nitro compounds. It is an antitumor drug and androgen antagonist. Nilumet is an antitumor hormone primarily used to treat prostate cancer. Nilumet is a pure nonsteroidal antiandrogen with an affinity for androgen receptors (but no affinity for progesterone, estrogen, or glucocorticoid receptors). Therefore, nilumet blocks the effects of androgens from the adrenal glands and testes, which stimulate the growth of both normal and malignant prostate tissue. Most prostate cancers are androgen-dependent and can be treated with surgical or medical castration. To date, antiandrogen monotherapy has not been proven to be as effective as castration. Nilumet is an androgen receptor inhibitor. Its mechanism of action is as an androgen receptor antagonist. Nilumet is a first-generation oral nonsteroidal antiandrogen drug with a structure similar to flutamide, used to treat prostate cancer. The incidence of elevated serum transaminases during nilumethoxazole treatment is low, and clinically significant acute liver injury is extremely rare. Nilumethoxazole is a synthetic nonsteroidal anti-androgen. It preferentially binds to androgen receptors and blocks the activation of these receptors by testosterone and other androgens; the drug inhibits androgen-dependent growth of normal and neoplastic prostate cells. (NCI04) Nilumethoxazole is an anti-tumor hormone primarily used to treat prostate cancer. It is a pure nonsteroidal anti-androgen with an affinity for androgen receptors (but no affinity for progesterone, estrogen, or glucocorticoid receptors). Therefore, nilumethoxazole blocks the effects of adrenal and testicular androgens that stimulate the growth of normal and malignant prostate tissue. Most prostate cancers are androgen-dependent and can be treated with surgical or medical castration. To date, anti-androgen monotherapy has not been proven to be as effective as castration therapy. Drug Indications For use in combination with surgical castration for the treatment of metastatic prostate cancer, including distant lymph node, bone, or visceral organ metastases (stage D2). FDA Label Mechanism of Action Nilumet competitively binds to androgen receptors, thereby blocking the effects of adrenal and testicular androgens that stimulate the growth of both normal and malignant prostate tissue. This blocking of androgen receptors may lead to tumor growth arrest or temporary regression by inhibiting androgen-dependent DNA and protein synthesis. Pharmacodynamics Nilumet is an anti-tumor hormone primarily used to treat prostate cancer. Nilumet is a pure nonsteroidal anti-androgen with an affinity for androgen receptors (but no affinity for progesterone, estrogen, or glucocorticoid receptors). Therefore, nilumet blocks the effects of adrenal and testicular androgens, thereby inhibiting the growth of both normal and malignant prostate tissue. Prostate cancer is primarily androgen-dependent and can be treated with surgical or medical castration. To date, anti-androgen monotherapy has not been proven to be comparable to castration in efficacy. Nilumet has a lower relative binding affinity to androgen receptors than bicalutamide, but similar to hydroxyflutamide.
Nilutamide is an FDA-approved drug for the treatment of metastatic prostate cancer. It is typically used in combination with surgical or medical castration. Its use has declined due to the availability of newer antiandrogens with more favorable safety profiles.

C12H10F3N3O4

317.2207

317.062

63612-50-0

Nilutamide-d6;1189477-66-4

4493

Light yellow to yellow solid powder

1.5±0.1 g/cm3

1490C

1.524

2.23

1

7

1

22

515

0

XWXYUMMDTVBTOU-UHFFFAOYSA-N

InChI=1S/C12H10F3N3O4/c1-11(2)9(19)17(10(20)16-11)6-3-4-8(18(21)22)7(5-6)12(13,14)15/h3-5H,1-2H3,(H,16,20)

5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 250 mg/mL (~788.10 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.56 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 20.8 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.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (6.56 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 20.8 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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.56 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)