Microbial Transformation of Flutamide

Flutamide (1), a nonsteroidal antiandrogen is a commonly used drug to treat advanced prostate cancer, which is one of the leading causes of death in men in the United States [1]. It is absorbed rapidly from the gastrointestinal track of humans and rats after oral administration and undergoes extensive metabolism in the liver through hydrolysis, hydroxylation, N-acetylation and nitroreduction to yield several metabolites [2]. The use of flutamide as therapeutic agent against prostrate cancers is eclipsed by rare incidences of idiosyncratic liver injury [2]. Although it is suggested that flutamide and its toxic metabolites could be responsible for such hepatic injury the mechanism of toxicity remains presently unknown. In the present investigation we used microbial models retrospectively in an attempt to obtain mammalian metabolites of flutamide which may help to identify factors responsible for toxicity. Microbial transformation studies using Rhodotorula mucilaginosa culture led to the isolation and characterization of important metabolites of flutamide (2–4) which were detected as products in vitro and in vivo experiments as well [2]. It shows that such investigations carried out prospectively could give valuable information about the activity and possible toxicity of a drug before designing more expensive and elaborate experiments.

Fig.1: Possible metabolic pathway of flutamide in R. mucilaginosa

Acknowledgements: This research is supported in part by the United States Department of Agriculture, Agricultural Research Service, Specific Cooperative Agreement No.58–6408–2-0009. References: [1] Sortino S, Gluffrida S, et al. (2001) Photochem Photobiol 73: 6–13. [2] Wen B, Coe KJ, et al. (2008) Chem res Toxicol 21: 2393–2406.