Systemic delivery of the GnRH antagonist cetrorelix by intratracheal instillation in anesthetized rats

Pulmonary absorption of the decapeptide cetrorelix acetate was studied in rats by a non-surgical intratracheal instillation method. The pharmacological effect (decrease of testosterone plasma concentration) following intratracheal (i.t.) instillation was determined in four groups of seven rats each at three different concentrations (0.5, 1.0 and 2.5 mg/kg body weight). The applied doses reduced testosterone plasma concentration to subnormal level (≤1 ng/ml), for 24, 34 and 72 h, respectively. Pharmacokinetic data of cetrorelix were determined in two additional groups of ten and nine rats, respectively, at doses of 0.5 and 1 mg/kg body. After i.t. administration the mean terminal t 1/2 was 12.94±1.74 (0.5 mg/kg) and 13.03±3.15 h (1 mg/kg); mean residence time (MRT) was 6.85±3.01 and 8.72±2.33 h; the C max (277.72±252.11 and 274.23±113.49 ng/ml) were observed in the first or the second plasma sample, suggesting that the drug was rapidly absorbed ( t=1 and 2 h). Comparing the plasma concentration after i.t. administration with data after i.v. administration from a previous study undertaken in the same laboratory, the mean i.t. bioavailability was calculated as 75.80±45.42 and 58.97±18.25%. The data from the group of 0.5 mg/kg were confirmed in a subsequent experiment. Our studies show that intratracheal instillation via the adopted method of non-surgical cannulation provides reproducible results. In addition, we demonstrated that pharmacologically active amounts of cetrorelix were absorbed from the lungs.