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

Pulmonary absorption of the decapeptide cetrorelix acetate was studied in r ats by a non-surgical intratracheal instillation method. The pharmacologica l effect (decrease of testosterone plasma concentration) following intratra cheal (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 (less than or equal to 1 ng/ml), for 24, 34 and 72 h, respectively. Pharma cokinetic data of cetrorelix were determined in two additional groups of te n 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 observ ed in the first or the second plasma sample, suggesting that the drug was r apidly 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 calcul ated 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 intrat racheal instillation via the adopted method of non-surgical cannulation pro vides reproducible results. In addition, we demonstrated that pharmacologic ally active amounts of cetrorelix were absorbed from the lungs. (C) 2000 El sevier Science B.V. All rights reserved.