Pharmacokinetics of detirelix following intratracheal instillation and aerosol inhalation in the unanesthetized awake sheep.

The unanesthetized awake sheep was employed as large animal model for the determination of bioavailability and pharmacokinetics following the pulmonary instillation of the decapeptide detirelix. After intratracheal administration of a 80 micrograms/kg dose, the average t1/2 of elimination was 9.8 +/- 1.3 hours (n = 5) which was similar to the elimination kinetics of a 30 micrograms/kg i.v. dose (7.2 +/- 2.9 hours). Mean residence time (MRT) was prolonged to 10.3 +/- 2.0 hours vs. 2.7 +/- 0.8 hours i.v., and mean absorption time (MAT) was calculated to be 7.5 +/- 1.8 hours. Maximum plasma levels (cmax) of 9.2 ng/ml were reached after 2 hours. The average bioavailability was 9.8 +/- 3.9% of the dose. The pharmacokinetic profile was found to be similar after aerosol administration. It was concluded that detirelix was absorbed systemically when administered by pulmonary instillation or aerosolization and that the unanesthetized awake sheep is a suitable model to study resulting drug profiles.