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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 alpha, alpha, alpha-trifluoro-4'-amino-m-acetotoluidide (A); alpha, alpha, alpha-trifluoro-4'-amino-2-methyl-m-lactotoluidide (B); alpha, alpha, alpha-trifluoro-4'-nitro-m-acetotoluidide (C); alpha, alpha, alpha-trifluoro-2-methyl-4'-nitro-m-lactotoluidide (D); alpha, alpha, alpha-trifluoro-4'-amino-2-methyl-m-propionotoluidide (E); and alpha, alpha, alpha-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, alpha, alpha, alpha-trifluoro-amino-5-nitro-p-cresol (G), accounts for 27% of urine 14C.
Insights
Topical flutamide (nonsteroid antiandrogen) absorption in men is at least 16%, with significant drug remaining at the application site. Flutamide is rapidly metabolized, with metabolite (D) becoming dominant within 24 hours.
Area of Science:
- Pharmacokinetics
- Dermatology
- Andrology
Background:
- Flutamide is a nonsteroid antiandrogen used in treating prostate cancer.
- Understanding the topical absorption and metabolism of flutamide is crucial for optimizing its therapeutic use and safety profile.
Purpose of the Study:
- To determine the absorption, distribution, and metabolism of flutamide following a single topical application in men.
- To identify and quantify flutamide and its metabolites in plasma and urine over a 120-hour period.
Main Methods:
- Administration of a single 6-hour topical application of 5 mg of 14C-labeled flutamide in an ethanol/propylene glycol solution.
- Collection and analysis of urine samples from 0 to 120 hours post-application.
- Serial blood sampling to determine flutamide and metabolite plasma concentrations.
- Recovery of drug from the application site using cotton swabs.
Main Results:
- At least 16% of the applied flutamide was absorbed into circulation.
- 56% of the applied dose was recovered from the application site.
- Flutamide plasma levels peaked at 4-6 hours and declined rapidly; by 6 hours, only 13% of plasma radioactivity was unchanged flutamide.
- At least 10 plasma metabolites were detected, with alpha, alpha, alpha-trifluoro-2-methyl-4'-nitro-m-lactotoluidide (D) identified as the major metabolite.
- Metabolite (D) exceeded flutamide concentrations between 8 and 24 hours post-application.
- Metabolite (G) accounted for 27% of the total radioactivity in urine.
Conclusions:
- Topical flutamide demonstrates significant absorption and rapid metabolism in men.
- The pharmacokinetic profile suggests extensive biotransformation, with several metabolites identified.
- Further research is warranted to elucidate the specific roles and toxicological profiles of these metabolites.