Chemical Properties
Light Yellow Solid
Uses
Antiandrogen; antineoplastic (hormonal).
Uses
Flutamide is a nonsteroidal antiandrogen drug; antineoplastic (hormonal).
Originator
scheting (USA)
Definition
ChEBI: Flutamide is a monocarboxylic acid amide and a member of (trifluoromethyl)benzenes. It has a role as an androgen antagonist and an antineoplastic agent.
Indications
Flutamide (Eulexin) is a nonsteroidal androgen receptor
antagonist that inhibits androgen binding to its
nuclear receptor. It is effective in inducing prostatic regression
and is approved for the treatment of prostatic
carcinoma. For maximum clinical effectiveness it has to
be used in combination with a GnRH antagonist (e.g.,
leuprolide acetate) that inhibits androgen production.
Flutamide may eventually be used for the treatment of
hirsutism and male pattern baldness in women if a topical
preparation is developed.
Indications
Flutamide (Eulexin) is a nonsteroidal antiandrogen compound that competes with testosterone
for binding to androgen receptors. The drug is well absorbed
on oral administration. It is an active agent in
the hormonal therapy of cancer of the prostate and has
been shown to complement the pharmacological castration
produced by the gonadotropin-releasing hormone
(GnRH) agonist leuprolide. Flutamide prevents the
stimulation of tumor growth that may occur as a result
of the transient increase in testosterone secretion after
the initiation of leuprolide therapy. The most common
side effects of flutamide are those expected with androgen
blockade: hot flashes, loss of libido, and impotence.
Mild nausea and diarrhea occur in about 10% of patients.
Indications
Flutamide is a prodrug possessing only weak androgen antagonistic activity of its own. It is oxidized in vivo to the active principle hydroxyflutamide (6) as primary metabolite.The elimination half-life of hydroxyflutamide is relatively short, 4–6.6 h in patients after a single oral 250 mg dose of flutamide. Therefore, oral dosing of 250 mg flutamide three times daily was applied clinically. The first introduction into clinical studies was achieved in 1975 as single agent in the first-line treatment of advanced prostate carcinoma. In the United States, flutamide was finally approved by FDA in 1989 for the treatment of metastatic prostate cancer in combination with a luteinizing hormone-releasing hormone (LHRH, also referred to as gonadotropin-releasing hormone (GnRH)) agonist, for instance, leuprorelin acetate (Leuprolide(R), Lupron(R)) or goserelin acetate (Zoladex(R)).The combined androgen blockade by flutamide plus an LHRH agonist or surgical castration was introduced in order to maximize the effects of androgen ablation. Flutamide also inhibits the secretion of androgens from the adrenal gland, which is not impaired by chemical castration with LHRH agonists or by surgical castration. In addition, the AR antagonist avoids the unacceptable initial tumor flare that occurs when LHRH agonists are given alone.
Favorable response to flutamide was seen with advanced prostate carcinoma patients after single-agent treatment as well as after combination treatment. The progression of the disease was slowed and the lifetime of patients was extended. For instance, the National Cancer Institute (NCI) initiated a trial (INT-0036) and concluded that the combination of leuprolide with flutamide was more effective than leuprolide alone in patients with advanced prostate cancer. However, significant side effects were also reported.The most frequently observed adverse events are summarized in Table 1. Flutamide evidently amplifies some of the LHRH agonist-induced side effects.
Table 1 Side effects of LHRH antagonist alone and in combination with flutamide.
Manufacturing Process
To a stirred, cooled solution of 100 g of 4-nitro-3-trifluoromethylaniline in 400 ml of pyridine, slowly and in a dropwise fashion, add 54 g of isobutyrylchloride and then heat the reaction mixture on a steam bath for 1.5 hours. Cool and pour the resulting mixture into ice water, filter and waterwash the crude anilide and crystallize the product of this example from benzene to obtain analytically pure material, MP 111.5°C to 112.5°C.
Brand name
Eulexin (Schering);DROGENIL.
Therapeutic Function
Antiandrogen
General Description
Flutamide, 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide, is dosed 3 times daily(250-mg dose; 750-mg total daily dose). A major metaboliteof flutamide, hydroxyflutamide, is a more potent AR antagonistthan the parent compound. This metabolite, which ispresent at a much higher steady-state concentration than isflutamide, contributes a significant amount of the antiandrogen action of this drug. A limiting factor in the useof flutamide is hepatotoxicity in from 1% to 5% of patients.Although the hepatotoxicity usually is reversible followingcessation of treatment, rare cases of death associated withhepatic failure have been reported to be associated with flutamidetherapy. Diarrhea is also a limiting side effect withflutamide therapy for some patients.
Biochem/physiol Actions
Flutamide is a non-steroidal anti-androgen drug. It consists of a nitroaromatic structure. Flutamide is a potent competitor of testosterone and dihydrotestosterone receptors. It is a potent hepatotoxin.
Mechanism of action
Flutamide is a nonsteroid drug that possesses antiandrogenic action. It blocks androgens
from binding with target tissues, thus preventing androgen action. The mechanism of
action is possibly also linked with a halt in dihydrotestosterone transport. It facilitates a
reduction in size and density of the prostate gland, and it reduces the amount of metastases
in such cancer, for which it is used in palliative treatment of prostate gland cancer.
Clinical Use
Flutamide is a pure antagonist, whereas 2-hydroxyflutamide is a more potent AR antagonist but also can activate the androgenic receptor at higher concentrations. These findings raise the possibility that increased conversion of flutamide to 2-hydroxyflutamide or accumulation of 2-hydroxyflutamide in cells may contribute to the anomalous responses to flutamide that are observed in some advanced prostate cancers.
Synthesis
Flutamide, 4-nitro-3-trifluoromethylisobutyranilide (29.2.15), a nonsteroid
antagonist of androgens, is made by acylating 4-nitro-3-trifluoromethylaniline with isobutyric acid chloride.
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: effects of coumarins enhanced
Metabolism
It is rapidly and extensively metabolised; the
major metabolite (2-hydroxyflutamide) possesses
anti-androgenic properties. Both flutamide and
2-hydroxyflutamide are more than 90% bound to plasma
proteins.Excretion is mainly in the urine with only minor amounts
appearing in the faeces
