Microbial Metabolism. Part 11. Metabolites of Flutamide

Abstract

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...

Production of human metabolites of the anti-cancer drug flutamide via biotransformation in Cunninghamella species

“…The compounds M3 and M4 required silylation prior to GC-MS analysis; M3 had a similar mass spectrum to 2-hydroxyflutamide, thus is probably another mono-hydroxylated metabolite, and the molecular ion of M4 was identical to silylated 2-methyl-N-[4-amino-3-(trifluoromethyl)phenyl]propanamide. In the recent study by (Herath and Khan 2010), the yeast Rhodotorula mucilaginosa (and other fungi that they investigated) produced two of the same metabolites that were identified here, M2 and M4, and these authors suggested that fungal metabolism of flutamide occurs exclusively via amide bond cleavage. Here, we have shown that in Cunninghamella sp.…”

“…There are a few studies on the degradation of trifluoromethyl-containing xenobiotics, for example, Engesser et al (1988 and1990) reported the metabolism of 3-and 4-trifluoromethyl benzoate in Pseudomonas putida, via the corresponding catechols, to 2-hydroxy-6-oxo-7,7,7-trifluoro-hepta-2,4-dienoate. Herath and Khan (2010) examined the biotransformation of flutamide in 40 microorganisms, and demonstrated the production of three metabolites also found in mammals, which arose via nitroreduction, hydrolysis and acetylation. However, 2-hydroxyflutamide, which is a major metabolite in human plasma (Aizawa et al 2003), was not observed in these fungal cultures, presumably because the enzyme required, cytochrome P450 (CYP1A2), was not produced by the fungi investigated.…”

Co-based heterogeneous catalysts from well-defined α-diimine complexes: Discussing the role of nitrogen

“…The pharmaceutically important substrates nitroresorcinol (1aa) and Flutamide (1ab) were also investigated in the catalytic hydrogenation ( Figure 9). The corresponding reduction products are key-intermediates in the preparation of biologically active compounds and are valuable starting molecules in total syntheses [84][85][86][87][88][89][90]. In the case of 1aa, the reaction was slow using EtOH-H2O 20:1 as solvent mixture but proceeded faster in a reaction media almost exclusively composed of water.…”

The biodegradation vs. biotransformation of fluorosubstituted aromatics

“…Up to three metabolites were identified, the major being the hydrolysis product 4-nitro-3-(trifluoromethyl)aniline in all flutamide transforming strains (Herath and Khan 2010). This metabolite was produced by C. elegans, too, along with 2-hydroxyflutamide and the product of nitro reduction.…”