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Research ArticleArticle

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

Rika Goda, Daichi Nagai, Yuji Akiyama, Kiyohiro Nishikawa, Isao Ikemoto, Yoshio Aizawa, Kiyoshi Nagata and Yasushi Yamazoe
Drug Metabolism and Disposition May 2006, 34 (5) 828-835; DOI: https://doi.org/10.1124/dmd.105.008623
Rika Goda
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Daichi Nagai
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Yuji Akiyama
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Kiyohiro Nishikawa
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Isao Ikemoto
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Yoshio Aizawa
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Kiyoshi Nagata
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Yasushi Yamazoe
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Abstract

Flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide), a nonsteroidal antiandrogen, is used in the treatment of prostate cancer but is occasionally associated with hepatic dysfunction. In the present study, the metabolism of flutamide including the formation of the possible reactive toxic metabolites was investigated using human liver microsomes and 10 isoforms of recombinant human cytochrome P450 (P450). 2-Hydroxyflutamide (OH-flutamide) and 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) were the main products of flutamide metabolism in human liver microsomes. The formation of OH-flutamide was markedly inhibited by ellipticine, an inhibitor of CYP1A1/1A2, and was mainly catalyzed by the recombinant CYP1A2. FLU-1 was also produced from OH-flutamide, but its metabolic rate was much less than that from flutamide. An inhibitor of carboxylesterase, bis-(p-nitrophenyl)phosphoric acid, completely inhibited the formation of FLU-1 from flutamide in human liver microsomes. A new metabolite, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine (FLU-1-N-OH), was detected as a product of the reaction of FLU-1 with human liver microsomes and identified by comparison with the synthetic standard. The formation of FLU-1-N-OH was markedly inhibited by the addition of miconazole, an inhibitor of CYP3A4, and was mediated by recombinant CYP3A4. Furthermore, FLU-1-N-OH was detected mostly as the conjugates (glucuronide/sulfate) in the urine of prostate cancer patients collected for 3 h after treatment with flutamide. The formation of FLU-1-N-OH, however, did not differ between patients with and without abnormalities of hepatic functions among a total of 29 patients. The lack of an apparent association of the urinary excretion of FLU-1-N-OH and hepatic disorder may suggest the involvement of an additional unknown factor in the mechanisms of flutamide hepatotoxicity.

Footnotes

  • This work was supported by grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labour and Welfare of Japan, and the Japan Health Sciences Foundation.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.008623.

  • ABBREVIATIONS: OH-flutamide, 2-hydroxyflutamide; P450, cytochrome P450; FLU-1, 4-nitro-3-(trifluoromethyl)phenylamine; FLU-3, 2-amino-5-nitro-4-(trifluoromethyl)phenol; FLU-2, N-[4-nitro-3-(trifluoromethyl)phenyl]-acetamide; FLU-1-N-OH, N-[4-nitro-3-(trifluoromethyl)phenyl]-hydroxylamine; FLU-4, N-[4-amino-3-(trifluoromethyl)phenyl]-acetamide; FLU-5, 2-hydroxy-2-methyl-N-[4-amino-3-(trifluoromethyl)-phenyl]propanamide; FLU-6, 2-methyl-N-[4-amino-3-(trifluoromethyl)-phenyl]-propanamide; FLU-N-OH, N-hydroxy-N-[4-nitro-3-(trifluoromethyl)-phenyl]isobutyramide; OH-FLU-N-OH, 2,N-dihydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propionamide; FLU-2-N-OH, N-hydroxy-N-[4-nitro-3-(trifluoromethyl)phenyl]acetamide; ESI, electrospray ionization; BNPP, bis-(p-nitrophenyl)phosphoric acid; LC/MS, liquid chromatography/mass spectrometry.

    • Received November 28, 2005.
    • Accepted February 15, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (5)
Drug Metabolism and Disposition
Vol. 34, Issue 5
1 May 2006
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DETECTION OF A NEW N-OXIDIZED METABOLITE OF FLUTAMIDE, N-[4-NITRO-3-(TRIFLUOROMETHYL)PHENYL]HYDROXYLAMINE, IN HUMAN LIVER MICROSOMES AND URINE OF PROSTATE CANCER PATIENTS
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Research ArticleArticle

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

Rika Goda, Daichi Nagai, Yuji Akiyama, Kiyohiro Nishikawa, Isao Ikemoto, Yoshio Aizawa, Kiyoshi Nagata and Yasushi Yamazoe
Drug Metabolism and Disposition May 1, 2006, 34 (5) 828-835; DOI: https://doi.org/10.1124/dmd.105.008623

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Research ArticleArticle

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

Rika Goda, Daichi Nagai, Yuji Akiyama, Kiyohiro Nishikawa, Isao Ikemoto, Yoshio Aizawa, Kiyoshi Nagata and Yasushi Yamazoe
Drug Metabolism and Disposition May 1, 2006, 34 (5) 828-835; DOI: https://doi.org/10.1124/dmd.105.008623
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