DETECTION OF A NEW <i>N</i>-OXIDIZED METABOLITE OF FLUTAMIDE, <i>N</i>-[4-NITRO-3-(TRIFLUOROMETHYL)PHENYL]HYDROXYLAMINE, IN HUMAN LIVER MICROSOMES AND URINE OF PROSTATE CANCER PATIENTS

Goda, Rika; Nagai, Daichi; Akiyama, Yuji; Nishikawa, Kiyohiro; Ikemoto, Isao; Aizawa, Yoshifusa; Nagata, Kiyoshi; Yamazoe, Yasushi

doi:10.1124/dmd.105.008623

Cited by 52 publications

(37 citation statements)

References 17 publications

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“…The three metabolites isolated and characterized were detected as products in vitro and in vivo experiments as well. 3,4,[6][7][8] The major routes of flutamide metabolism in humans include P450 mediated oxidation to 2-hydroxyflutamide and cleavage of the amide bond to FLU-1. 3) In addition to 2-hydroxyflutamide mono-, di-and trihydroxylated flutamides have been identified.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

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confidence: 98%

“…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.…”

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confidence: 99%

“…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.…”

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confidence: 99%

“…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.…”

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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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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Microbial Metabolism. Part 11. Metabolites of Flutamide

Herath

Khan

2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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CytochromeP450 Enzymes

Hrycay

Bandiera

2010

Pharmaceutical Sciences Encyclopedia

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The cytochrome P450 (CYP) enzymes, also known as the microsomal mixed function oxidase system, are the predominant biotransformation pathway in the body for lipid‐soluble endogenous and xenobiotic compounds. CYP enzymes play a key role in the biotransformation of pharmaceutical agents and thus are major determinants of duration of action and clearance of drugs. This article focuses on the characterization, function, and regulation of CYP enzymes that are relevant to our understanding of how CYP enzymes can metabolize a large variety of drugs.

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