The pharmacokinetics of flutamide and its major metabolites after a single oral dose and during chronic treatment

Abstract

Flutamide is a nonsteroidal antiandrogen used in the treatment of prostatic carcinoma. We have investigated the disposition of flutamide and its two major metabolites in ten urological in-patients without significant liver or renal disease. After oral administration flutamide is absorbed from the gastrointestinal tract with a t_max of about 2 h. Flutamide undergoes extensive first-pass metabolism, and its major metabolites are 2-hydroxyflutamide and the hydrolysis product 3-trifluoromethyl-4-nitroaniline. After the oral administration of a single dose of 250 mg or 500 mg maximum flutamide plasma concentrations of 0.02 and 0.1 µg·ml⁻¹ respectively were observed. Maximum plasma concentrations of 2-hydroxylfutamide for the same flutamide doses were 1.3 and 2.4 µg·ml⁻¹ (mean ofn=2 orn=3). Steady-state concentrations of the biologically active metabolite 2-hydroxyflutamide (0.94±0.23 µg·ml⁻¹, mean±SD,n=5) were found at 2–4 days after the administration of 250 mg every 8 h. The area under the plasma concentration time curve for 2-hydroxyflutamide averaged 11.4 (10.6 and 12.1) and 24.3 (21.5–29.4,n=3) µg·ml⁻¹·h for 250 mg and 500 mg flutamide orally. 2-Hydroxyflutamide and 3-trifluoromethyl-4-nitroaniline were eliminated monoexponentially with half-times of 4.3–21.9 and 4.3–17.2 h (n=5) respectively.