PULMONARY DELIVERY OF THE 5-LIPOXYGENASE INHIBITOR, ABBOTT-85761, IN BEAGLE DOGS

Abbott-85761 is a potent 5-lipoxygenase inhibitor which is currently u nder investigation for the treatment of asthma. With a primary objecti ve of targeting this compound to the lung and reducing systemic exposu re, studies were undertaken to assess its lung delivery from a metered -dose inhalation (MDI) aerosol. Pulmonary absorption characteristics o f Abbott-85761 from an intratracheally (I.T.) instilled aqueous soluti on at doses of 0.25, 0.50 and 0.75 mg/kg were ascertained. Using trach eostomized beagle dogs, and a parallel three-way crossover study desig n, the I.T. results were compared with equivalent doses of intravenous ly (I.V.) administered drug. Plasma drug concentrations were analyzed using a reverse-phase HPLC assay. Despite limited aqueous solubility, Abbott-85761 was rapidly absorbed from the lung after I.T. instillatio n, with complete absorption occurring within 15-30 min after dosing. A linear dose proportionality as a function of AUC was observed for I.V . as well as I.T. treatments, with pulmonary bioavailability approxima ting 80%. The MDI formulation contained 10 mg/ml drug in tetrafluoroet hane (HFC-134a). In vitro tests for functional performance (dispersion quality, dose delivery, content uniformity and particle size) reveale d a homogeneous, physically stable and a nearly monodispersed formulat ion. In vivo bioavailability studies were thus conducted using a three -way crossover study design, evaluating 0.5 mg/kg aerosolized Abbott-8 5761 and equivalent oral and I.V. dosages of the drug. Results demonst rated that the aerosol formulation was slowly absorbed from the lung. Plasma T-max was approximately 7 h with pulmonary bioavailability abou t 40% compared to I.V. administration. The results are discussed in th e context of formulation effects and delivery technique on pulmonary a bsorption of A-85761. (C) 1997 Elsevier Science B.V.