Systemic delivery of cetrorelix to rats by a new aerosol delivery system

Purpose. To study the pulmonary absorption and tolerability of various form ulations of the decapeptide cetrorelix acetate in rats by a new aerosol del ivery system (ASTA-ADS) for intratracheal application. Methods. Using the ASTA-ADS, cetrorelix liquid formulations (aqueous soluti ons for ultrasonic nebulization) were firstly selected and subsequently del ivered as nebulized aerosol to orotracheally cannulated rats. The pharmacol ogic effect (decrease of testosterone serum level) of four cetrorelix formu lations was determined in rats by enzyme linked immunosorbant assay, and ph armacokinetic data were determined after measurement of cetrorelix serum le vel by radioimmunoassay. Histological examination of the lung was performed at the end of the experiments, and in a supplementary experiment the respi ratory parameters (resistance and compliance) of rats were monitored by a v alidated pulmonary monitoring system during the aerosol application of the same formulations. Results. After an exposure time of 5 min, the applied formulations reduced the testosterone concentration in serum to subnormal levels (less than or e qual to1 ng/ml) over a period of 24 h. Comparing the plasma concentration a fter intratracheal aerosolization with data of intravenous administration, the mean calculated bioavailabilities for the four formulations using the c orrected dose (delivered-exhaled amount) were between 48.4 +/- 27.0% and 77 .4 +/- 44.0%. The histologic examination of the lungs revealed different to lerability of the various tested formulations ranging from locally intolera ble to well tolerated. The measurement of the lung function parameters did not reveal any compound or formulation related changes. Conclusions. Our studies show that cetrorelix can be effectively administer ed as aerosol and that intratracheal aerosolization via the ASTA-ADS provid es results that are well comparable to other application routes, as demonst rated by statistical comparison of the newly obtained data with previous re sults from intratracheal instillation of cetrorelix solutions in rats.