In Vitro Effects of Fluoroquinolone Anti-bacterial Agents on Flutamide Metabolism in Human Liver Microsomes.

Watanabe, Noriko; Goda, Rika; Irie, Tsuyoshi; Yamashita, Kouwa

doi:10.3999/jscpt.32.2_65

Cited by 6 publications

(10 citation statements)

References 1 publication

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“…The formation of OH-flutamide from flutamide in the human liver is predominantly mediated by CYP1A2. This is concordant with earlier studies (Schulz et al, 1988;Shet et al, 1997;Watanabe et al, 2001). In the present study, flutamide was shown to undergo deamidation to FLU-1 by a carboxylesterase.…”

Section: Substratesupporting

confidence: 82%

“…1 (Asakawa and Yamashita, 1995). A major metabolite in plasma is 2-hydroxyflutamide (OH-flutamide), whose formation from flutamide is catalyzed by CYP1A2 (Shet et al, 1997;Watanabe et al, 2001). In addition, another metabolite, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1), was detected as a major metabolite in plasma (Schulz et al, 1988), whereas the main metabolite in urine is 2-amino-5-nitro-4-(trifluoromethyl)phenol (FLU-3), which accounts for 50 to 90% of urinary excretion (Asakawa and Yamashita, 1995).…”

Section: Flutamidementioning

confidence: 99%

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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

Goda

Nagai²,

Akiyama³

et al. 2006

Drug Metab Dispos

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Section: Substratesupporting

confidence: 82%

Section: Flutamidementioning

confidence: 99%

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

Goda

Nagai²,

Akiyama³

et al. 2006

Drug Metab Dispos

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“…Flutamide undergoes extensive hepatic first-pass metabolism in humans and rats. The primary route of metabolism is the CYP1A2-mediated oxidation to 2-hydroxyflutamide, although the formation of other oxidative metabolites and the involvement of CYP1A1 and CYP1B1 in the metabolism of flutamide have also been reported (Katchen and Buxbaum, 1975;Schulz et al, 1988: Shet et al, 1997: Watanabe et al, 2001). 2-Hydroxyflutamide (M1; Scheme 1) appears to be largely responsible for the antiandrogenic activity of flutamide.…”

Section: Flutamidementioning

confidence: 99%

Identification of a Novel Glutathione Conjugate of Flutamide in Incubations with Human Liver Microsomes

Kang¹,

Dalvie²,

Smith³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Flutamide, a nonsteroidal antiandrogen drug widely used in the treatment of prostate cancer, has been associated with rare incidences of hepatotoxicity in patients. It is believed that bioactivation of flutamide and subsequent covalent binding to cellular proteins is responsible for its toxicity. Current in vitro studies were undertaken to probe the cytochrome P450 (P450)-mediated bioactivation of flutamide and identify the possible reactive species using reduced glutathione (GSH) as a trapping agent. NADPH-and GSH-supplemented human liver microsomal incubations of flutamide gave rise to a novel GSH conjugate where GSH moiety was conjugated to the flutamide molecule via the amide nitrogen, resulting in a sulfenamide. The structure of the conjugate was characterized by liquid chromatography-tandem mass spectrometry and NMR experiments. The conjugate formation was primarily catalyzed by heterologously expressed CYP2C19, CYP1A2, and, to a lesser extent, CYP3A4 and CYP3A5. The mechanism for the formation of this conjugate is unknown; however, a tentative bioactivation mechanism involving a P450-catalyzed abstraction of hydrogen atom from the amide nitrogen of flutamide and the subsequent trapping of the nitrogen-centered radical by GSH or oxidized glutathione (GSSG) was proposed. Interestingly, the same adduct was formed when flutamide was incubated with human liver microsomes in the presence of GSSG and NADPH. This finding suggests that P450-mediated oxidation of flutamide via a nitrogen-centered free radical could be one of the several bioactivation pathways of flutamide. Even though the relationship of the GSH conjugate to flutamide-induced toxicity is unknown, the results have revealed the formation of a novel, hitherto unknown, GSH adduct of flutamide.

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“…6,7 Serum concentration of OH-flutamide in patients with hepatic dysfunction were lower than in patients who maintained normal liver function, suggesting that the activation of flutamide into OH-flutamide was compromised in these patients. 16 It is known that CYP1A2 is induced by smoking, and that the risk for developing flutamide-induced hepatic injury is lower in smokers.…”

Section: Caffeine Test In Predicting Hepatic Injury S Ozono Et Almentioning

confidence: 99%

“…OH-flutamide, an active metabolite of flutamide, acts as a testosterone antagonist and exerts antiandrogenic action and this pathway of flutamide metabolism primarily involves CYP1A2. 6,7 Of the currently available methods of evaluating the activity of enzymes involved in drug metabolism in vivo, the caffeine test has been used as a non-invasive means of evaluating CYP1A2 activity. 8,9 The present investigation was conducted to examine the relationship between CYP1A2 activity, measured by the caffeine test, and liver enzyme markers in patients who had developed flutamide-induced hepatic injury.…”

Section: Introductionmentioning

confidence: 99%

Caffeine test in predicting flutamide-induced hepatic injury in patients with prostate cancer

Ozono

Yamaguchi

Mochizuki

et al. 2002

Prostate Cancer Prostatic Dis

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The caffeine test measures the activity of cytochrome P450 (CYP1A2) which is a major enzyme involved in the activation of flutamide. The usefulness of this test in predicting flutamide-induced hepatic injury in patients with prostate cancer was examined. The subjects were: (1) five patients whose aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level rose to 100 IU/l or higher following the start of flutamide (moderately injured group); (2) four patients whose AST and ALT levels were higher than normal but less than 100 IU/l (mildly injured group); and (3) two patients whose hepatic function remained normal (normal group). The subjects were each given canned coffee to drink. Urinary caffeine (137X), paraxanthine (17X) and 1, 7-dimethyluric acid (17U) levels were measured 4 -5 h later. The metabolite ratio, (17U þ 17X)/137X, was calculated to serve as an indicator of CYP1A2 activity. The metabolite ratio for the moderately injured group (3.98 AE 1.56) and the mildly injured group (5.55 AE 1.42) were lower than that for the normal group (9.56). The results suggest that a decrease in CYP1A2 activity is involved in the onset of flutamide-induced hepatic injury, and that the caffeine test seems to provide a useful means of its prediction.

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In Vitro Effects of Fluoroquinolone Anti-bacterial Agents on Flutamide Metabolism in Human Liver Microsomes.

Cited by 6 publications

References 1 publication

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

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

Identification of a Novel Glutathione Conjugate of Flutamide in Incubations with Human Liver Microsomes

Caffeine test in predicting flutamide-induced hepatic injury in patients with prostate cancer

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