Percutaneous penetration and metabolism of topical [14C] flutamide in men

Abstract

This study was designed to determine the fate of the nonsteroid antiandrogen flutamide in men following a single 6 hr topical application of 5 mg 14C labeled drug dissolved in 50% ethanol/50% propylene glycol. Analysis of 0-120 hr urine shows at least 16% of the applied flutamide is absorbed. Fifty six percent of the dose is recovered from the site of application with cotton swabs moistened with 50% ethanol/50% propylene glycol. Flutamide plasma levels peak in 4 to 6 hr at about 1.3 ng/ml and then decline rapidly to about 0.08 ng/ml 24 hr after application. Only 13% of plasma 14C is associated with flutamide 6 hr after drug application. There are at least 10 plasma metabolites, of which 6 have been tentatively identified. These are: α,α,α trifluoro 4' amino m acetotoluidide (A); α,α,α trifluoro 4' amino 2 methyl m lactotoluidide (B); α,α,α trifluoro 4' nitro m acetotoluidide (C); α,α,α trifluoro 2 methyl 4' nitro m lactotoluidide (D); ,α,α trifluoro 4' amino 2 methyl m propionotoluidide (E); and α,α,α trifluoro 6 nitro m toluidine (F). (D) is the major plasma metabolite, and its concentration exceeds flutamide's between 8 and 24 hr after drug. All the plasma metabolites are found in 0-24 hr urine in minor amounts. An additional metabolite, α,α,α trifluoro amino 5 nitro p cresol (G), accounts for 27% of urine 14C.