Pharmacokinetics of the anti-androgenic drug flutamide in healthy stallions

Alternatives to surgical castration are necessary for controlling the sexual behaviour of stallions with breeding potential in training and competition. Flutamide is a potent selective non-steroidal androgen receptor competitive antagonist that has been used in human beings as an anti-androgenic drug. In this study, the pharmacokinetics and bioavailability of flutamide and its main active metabolite, 2-hydroflutamide, were determined in seven healthy mature stallions. Single doses of flutamide (1 mg/kg intravenously, 1 mg/kg orally in fasted horses, 5 mg/kg orally in fasted horses and 5 mg/kg orally in fed horses) were administered randomly at intervals of 2 weeks. All horses had full physical examinations and blood samples were collected for pharmacokinetics, complete blood counts and biochemistry before and after drug administration. Administration of flutamide did not result in any abnormalities on physical examination or in blood parameters. After intravenous administration of flutamide, the volume of distribution was 0.83 L/kg and clearance was 1.20 L/h/kg. Flutamide and its metabolite had high protein binding values (93-97%). After oral administration, flutamide was rapidly transformed to 2-hydroxyflutamide, with areas under the concentration-time curve ratios of metabolite:drug similar to 7. Oral bioavailability was 6.63% after 1 mg/kg flutamide in fasted horses, 6.50% after 5 mg/kg flutamide in fasted horses and 6.95% after 5 mg/kg in fed horses. Half lives of flutamide were close to 1 h after intravenous administration and 2 h after oral administration. Half lives of 2-hydroxyflutamide were 4.79-6.84 h for all routes and doses. After oral administration, oral flutamide reached plasma concentrations that could be effective as an anti-androgenic agent in horses, but further studies are needed to determine whether flutamide has clinical value as an alternative to castration for controlling sexual behaviour in stallions. (C) 2017 Elsevier Ltd. All rights reserved.