Abstract
Flutamide is a potential antineoplastic drug classified as an anti-androgen. It is a therapy for men with advanced prostate cancer, administered orally after which it undergoes extensively first pass metabolism in the liver with the production of several metabolites. These metabolites are predominantly excreted in urine. One of the important metabolites in plasma is 4-nitro-3-(trifluoromethyl)phenylamine (Flu-1), while the main metabolite in urine is 2-amino-5-nitro-4-(trifluoromethyl)phenol (Flu-3). In this work the two metabolites, Flu-1 and Flu-3, have been synthesized, and then structural confirmation has been carried out by HNMR analysis. Efforts were exerted to develop chromatographic methods for resolving Flutamide and its metabolites with the use of acceptable solvents without affecting the efficiency of the methods. The drug along with its metabolites were quantitatively analyzed in pure form, human urine, and plasma samples using two chromatographic methods, HPTLC and HPLC–DAD methods. FDA guidelines for bio-analytical method validation were followed and USP recommendations were used for analytical method validation. Interference from excipients has been tested by application of the methods to pharmaceutical tablets. No significant difference was found between the proposed methods and the official one when they were statistically compared at p value of 0.05%.
Highlights
Flutamide has chemical structure of 2-methyl-N[4nitro-3-(trifluoromethyl)phenyl]propanamide [1]
Metabolism of Flutamide occurs by human liver microsomes after 1 h from oral administration with the production of many toxic metabolites. 4-nitro-3-(trifluoromethyl)phenylamine [Flu-1] is reported to be one of the important Flutamide plasma metabolites [5] and one of its impurities and related substances according to BP [6] and USP [7]
In BP [6] Flutamide was determined by a spectrophotometric method, while in USP [7] it was measured in both pure form and capsules by a RP-HPLC method using C18 column
Summary
Flutamide has chemical structure of 2-methyl-N[4nitro-3-(trifluoromethyl)phenyl]propanamide [1]. It is an acetanilide, non-steroidal orally active anti-androgen [2] used clinically for the management of metastatic carcinoma [3]. Metabolism of Flutamide occurs by human liver microsomes after 1 h from oral administration with the production of many toxic metabolites. 4-nitro-3-(trifluoromethyl)phenylamine [Flu-1] is reported to be one of the important Flutamide plasma metabolites [5] and one of its impurities and related substances according to BP [6] and USP [7]. Flutamide is a pharmacopoeial drug reported in BP [6] and USP [7]. In BP [6] Flutamide was determined by a spectrophotometric method, while in USP [7] it was measured in both pure form and capsules by a RP-HPLC method using C18 column
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