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

Kang, Ping; Dalvie, Deepak; Smith, Evan; Zhou, Sue; Deese, Alan

doi:10.1124/dmd.107.014860

Cited by 36 publications

(36 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the one characterized previously for the parent (Kang et al, 2007), we have identified several bioactivation pathways of flutamide metabolites in the present study. These results suggest that, in addition to the direct bioactivation of parent flutamide, flutamide metabolites could contribute to the Flu-6…”

Section: Discussionmentioning

confidence: 80%

“…CYP3A is the other major P450 isozyme responsible for the bioactivation of flutamide and subsequent covalent binding to liver proteins (Berson et al, 1993). However, there was only a marginal involvement of CYP3A4 in the formation of G1 and N-(glutathio-S-yl) flutamide adduct (Kang et al, 2007). CYP3A4 must play a major role in the bioactivation of other flutamide metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…M5 is a minor metabolite and only observed in human liver microsomal incubations. However a closer examination of the NADPH-supplemented human liver microsomal incubations of flutamide with GSH revealed that, in addition to the N-glutathionyl flutamide adduct identified in the previous report (Kang et al, 2007), another major GSH adduct (G1) was also formed, and it was later shown to be derived from M5.…”

Section: Bioactivation Of Flutamide Metabolitesmentioning

confidence: 99%

“…Similarly, Tevell and coworkers (Tevell et al, 2006) have detected a mercapturic acid conjugate of hydroxylated flutamide in the urine of prostate cancer patients. In a previous study of the bioactivation of flutamide in human liver microsomes, a novel N-S glutathionyl adduct was detected and fully characterized by MS and NMR, which is formed by the direct bioactivation of the parent drug (Kang et al, 2007).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Bioactivation of Flutamide Metabolites by Human Liver Microsomes

Kang¹,

Dalvie²,

Smith³

et al. 2008

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

ABSTRACT:Flutamide, a widely used nonsteroidal antiandrogen drug for 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. A novel N-S glutathione adduct has been identified in a previous bioactivation study of flutamide (Kang et al., 2007). Due to the extensive first pass metabolism, flutamide metabolites such as 2-hydroxyflutamide and 4-nitro-3-(trifluoromethyl)phenylamine (Flu-1) have achieved plasma concentrations higher than the parent in prostate cancer patients. In vitro studies in human liver microsomes were conducted to probe the cytochrome P450 (P450)-mediated bioactivation of flutamide metabolites and identify the possible reactive species using reduced glutathione (GSH) as a trapping agent. Several GSH adducts (G1, Flu-1-G1, Flu-1-G2, Flu-6-Gs) derived from the metabolites of flutamide were identified and characterized. A comprehensive bioactivation mechanism was proposed to account for the formation of the observed GSH adducts. Of interest were the formation of a reactive intermediate by the desaturation of the isopropyl group of M5 and the unusual bioactivation of Flu-1. Studies using recombinant P450s suggested that the major P450 isozymes involved in the bioactivation of flutamide and its metabolites were CYP1A2, CYP3A4, and CYP2C19. These findings suggested that, in addition to the direct bioactivation of flutamide, the metabolites of flutamide could also be bioactivated and contribute to flutamideinduced hepatotoxicity.2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide (flutamide), a widely prescribed nonsteroidal antiandrogen drug, has been shown to increase survival time of prostate cancer patients in combination therapy with luteinizing hormone-releasing agonists or orchiectomy (Brogden and Clissold, 1989;McLeod, 1993;Schmitt et al., 2001). However, a number of hepatotoxicity cases were reported to be associated with the clinical use of this drug, such as temporary increases in transaminase markers and rare incidences of severe liver dysfunction (Gomez et al

show abstract

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Bioactivation Of Flutamide Metabolitesmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Bioactivation of Flutamide Metabolites by Human Liver Microsomes

Kang¹,

Dalvie²,

Smith³

et al. 2008

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

confidence: 99%

Microbial Metabolism. Part 11. Metabolites of Flutamide

Herath

Khan

2010

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

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...

show abstract

Covalent Drug–Protein Adducts: An Exploration of Their Role in Drug‐Induced Liver and General Organ Toxicity

Evans

2012

Encyclopedia of Drug Metabolism and Interactions

View full text Add to dashboard Cite

Overcoming drug induced liver injury continues to represent a challenge for the pharmaceutical industry. Reducing metabolic drug bioactivation is a medicinal chemistry strategy that continues to represent the main platform to minimize this liability. Leveraging covalent binding studies to predict potential for liver toxicity has been widely investigated and appears to have some merit when performed in hepatocyte preparations and integrated with, for example, daily dose but clearly has limitations even when supplemented with data from additional assays that assess hepatotoxicity risk. Here we move beyond a discussion of acute liver toxicity as addressed by chemical synthetic strategies (focus on drug design) by exploring the underlying biochemical science and challenges that still exist regarding the predisposition of some people to idiosyncratic liver toxicity (focus on the individual). The hope is that the positive trajectory of the developing science in this area has the potential to deliver safer drugs to patients in need.

show abstract

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

Cited by 36 publications

References 23 publications

Bioactivation of Flutamide Metabolites by Human Liver Microsomes

Bioactivation of Flutamide Metabolites by Human Liver Microsomes

Microbial Metabolism. Part 11. Metabolites of Flutamide

Covalent Drug–Protein Adducts: An Exploration of Their Role in Drug‐Induced Liver and General Organ Toxicity

Contact Info

Product

Resources

About