Abstract

Abbott-85761 is a potent 5-lipoxygenase inhibitor which is currently under investigation for the treatment of asthma. With a primary objective of targeting this compound to the lung and reducing systemic exposure, studies were undertaken to assess its lung delivery from a metered-dose inhalation (MDI) aerosol. Pulmonary absorption characteristics of Abbott-85761 from an intratracheally (I.T.) instilled aqueous solution at doses of 0.25, 0.50 and 0.75 mg/kg were ascertained. Using tracheostomized beagle dogs, and a parallel three-way crossover study design, the I.T. results were compared with equivalent doses of intravenously (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. instillation, 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 approximating 80%. The MDI formulation contained 10 mg/ml drug in tetrafluoroethane (HFC-134a). In vitro tests for functional performance (dispersion quality, dose delivery, content uniformity and particle size) revealed a homogeneous, physically stable and a nearly monodispersed formulation. In vivo bioavailability studies were thus conducted using a three-way crossover study design, evaluating 0.5 mg/kg aerosolized Abbott-85761 and equivalent oral and I.V. dosages of the drug. Results demonstrated that the aerosol formulation was slowly absorbed from the lung. Plasma T max was approximately 7 h with pulmonary bioavailability about 40% compared to I.V. administration. The results are discussed in the context of formulation effects and delivery technique on pulmonary absorption of A-85761.

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