Automated determination of flutamide by a validated flow-injection method: Application to dissolution studies of pharmaceutical tablets

Tzanavaras, Paraskevas D.; Themelis, Demetrius G.

doi:10.1016/j.jpba.2006.11.039

Cited by 29 publications

(30 citation statements)

References 9 publications

(15 reference statements)

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“…6) Its activity is based on the ability to attach itself to the receptors of the cancer cells preventing the attachment of testosterone, the male hormone which is essential for the growth of the prostate cancer cells. Flutamide with the structure similar to that of testosterone 9) however, is a weak antiandrogen. 10) FLU-1, which is devoid of any antiandrogenic activity 7) is formed by carboxyesterase-catalysed hydrolysis.…”

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confidence: 99%

Microbial Metabolism. Part 11. Metabolites of Flutamide

Herath

Khan

2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Flutamide, a nonsteroidal antiandrogen is a commonly used drug to treat advanced prostate cancer, 2) which is one of the leading causes of death in men in the United States. 3) It is absorbed rapidly from the gastrointestinal track of humans and rats after oral administration and undergoes extensive metabolism in the liver [3][4][5] through hydrolysis, hydroxylation, N-acetylation and nitroreduction to yield several metabolites. 6) The major metabolites detected in plasma are 2-hydroxyflutamide (OH-FLU) and 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) 7) with concentrations higher than that of flutamide. 8) It is suggested that the antiandrogen activity of flutamide is largely associated with its main metabolite, 2-hydroxyflutamide. 6) Its activity is based on the ability to attach itself to the receptors of the cancer cells preventing the attachment of testosterone, the male hormone which is essential for the growth of the prostate cancer cells. Flutamide with the structure similar to that of testosterone 9) however, is a weak antiandrogen. 10) FLU-1, which is devoid of any antiandrogenic activity 7) is formed by carboxyesterase-catalysed hydrolysis. 6) It is a product of a clearance pathway. Thus, the main metabolite identified in urine is 2-amino-5-nitro-4-(trifluoromethyl)phenol (FLU-3). 3) However, urinary excretion is not a major pathway of flutamide elimination in humans. 7) The use of flutamide as therapeutic agent against prostrate cancers is eclipsed by rare incidences of idiosyncratic liver injury. 6) Although it is suggested that flutamide and its toxic metabolites could be responsible for such hepatic injury the mechanism of toxicity remains presently unknown. 6) It is observed that the serum concentration of FLU-1 is higher 3,7) and that of OH-flutamide is lower in patients with liver dysfunction than in those with normal liver function. 11) The formation of OH-flutamide from the parent compound is catalyzed by CYP1A2. Thus, a lower concentration of OH-flutamide is due to reduced activity of the enzyme. 11) Therefore, it is suggested that since CYP1A2 seems to be involved in the initiation of flutamide-induced liver injury, attention should be paid to patients with low CYP1A2 activity before administrating flutamide. 11) Genetic mutations and factors such as smoking, food and drugs are shown to influence the activity of the enzyme. 11) Smoking induces CYP1A2 activity and reduces the risk of liver toxicity due to flutamide. 3) In the present investigation we used microbial models retrospectively in an attempt to obtain mammalian metabolites of 1. No more than three metabolites were detected in the culture media of the forty microorganisms used. Among them the most prominent compound was FLU-1, detected in almost all the cultures used. Rhodotorula mucilaginosa culture which gave all three metabolites in good yields was selected for scale up studies. The structures of the metabolites (2-4) were elucidated by detailed study of their high resolution spectroscopic data. Results and DiscussionOf the for...

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confidence: 99%

Microbial Metabolism. Part 11. Metabolites of Flutamide

Herath

Khan

2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Other methods were published for determination of Flutamide including electrochemical [ 2 , 9 , 10 ], different spectrophotometric [ 2 , 8 , 11 – 14 ], spectrofluorimetric [ 15 ], and different chromatographic methods [ 2 , 3 , 16 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

Determination of flutamide and two major metabolites using HPLC–DAD and HPTLC methods

Abdelwahab

Elshemy

Farid

2018

Chemistry Central Journal

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Flutamide is a potential antineoplastic drug classified as an anti-androgen. It is a therapy for men with advanced prostate cancer, administered orally after which it undergoes extensively first pass metabolism in the liver with the production of several metabolites. These metabolites are predominantly excreted in urine. One of the important metabolites in plasma is 4-nitro-3-(trifluoromethyl)phenylamine (Flu-1), while the main metabolite in urine is 2-amino-5-nitro-4-(trifluoromethyl)phenol (Flu-3). In this work the two metabolites, Flu-1 and Flu-3, have been synthesized, and then structural confirmation has been carried out by HNMR analysis. Efforts were exerted to develop chromatographic methods for resolving Flutamide and its metabolites with the use of acceptable solvents without affecting the efficiency of the methods. The drug along with its metabolites were quantitatively analyzed in pure form, human urine, and plasma samples using two chromatographic methods, HPTLC and HPLC–DAD methods. FDA guidelines for bio-analytical method validation were followed and USP recommendations were used for analytical method validation. Interference from excipients has been tested by application of the methods to pharmaceutical tablets. No significant difference was found between the proposed methods and the official one when they were statistically compared at p value of 0.05%.

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“…Owning to its similar structure to testosterone, flutamide works as a competitive antagonist that blocks the attachment of the male hormone at the androgen receptor in the prostate [3,4]. Flutamide is rapidly metabolized to its active metabolite 2-hydroxyflutamide by extensive firstpass metabolism [5][6][7].…”

Section: Introductionmentioning

confidence: 99%