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 tmax 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 micrograms.ml-1 respectively were observed. Maximum plasma concentrations of 2-hydroxyflutamide for the same flutamide doses were 1.3 and 2.4 micrograms.ml-1 (mean of n = 2 or n = 3). Steady-state concentrations of the biologically active metabolite 2-hydroxyflutamide (0.94 +/- 0.23 micrograms.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) micrograms.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.

Pharmacologically Active Metabolites of Currently Marketed Drugs: Potential Resources for New Drug Discovery and Development

“…11,76) 2-Hydroxy‰utamide is a more potent androgen receptor antagonist than parent drug. It was reported that elimination half-life of 2-hydroxy‰utamide after oral administration was 2.7 h. 77,78) Irinotecan Irinotecan is a synthetic analog of naturally occurring alkaloid, camptothecin and has demonstrated pronounced antitumor activity against a variety of tumors. In humans, irinotecan is rapidly metabolized by an endogenous carboxylesterase present in the intestinal mucosa, plasma and liver into a highly active metabolite, SN-38.…”

A Simple, Fast, Low Cost, HPLC/UV Validated Method for Determination of Flutamide: Application to Protein Binding Studies

“…Its plasma peak concentration is achieved in 2 hours. 1 A single oral dose of 250 mg and 500 mg flutamide leads to maximum plasma concentration (C max ) of 0.02 µg ml ⁄ and 0.1 µg ml ⁄ respectively. 2 After a drug reaches to systemic circulation it can binds to plasma proteins to form drugprotein complexes.…”

“…4 The gas chromatographic determination of flutamide in blood was reported in 1988 by Schulz et al for a limited range of concentration (0.02-0.250 µg/ml). 1 In another study by Manjunath et al, HPLC system was equipped with a radioactive detector and a gradient solvent system was used for radioactive flutamide determination with 18.3 minutes retention time. 5 The HPLC analysis of flutamide in plasma were also carried out by Iwanaga et al on an separation module coupled to a dual wavelength absorbance detection system which is designed to provide the highest performance in UV-Visible detection and offers the superior sensitivity required for detection of minor impurities in complex applications.…”

Contributions of Arylacetamide Deacetylase and Carboxylesterase 2 to Flutamide Hydrolysis in Human Liver

“…Flutamide itself is not toxic when used at the appropriate clinical dose, but bioactivation of flutamide has been considered to be the cause of flutamide-induced hepatotoxicity (Fau et al, 1994). Flutamide is mainly metabolized to 2-hydroxyflutamide and 5-amino-2-nitrobenzotrifluoride (FLU-1) by human CYP1A2 and esterase(s), respectively (Katchen and Buxbaum, 1975;Schulz et al, 1988). It has been suggested that 2-hydroxyflutamide is associated with the therapeutic effect of flutamide (Katchen and Buxbaum, 1975), whereas FLU-1 is considered to have no therapeutic effect (Aizawa et al, 2003).…”