Pulmonary bioavailability and absorption characteristics of the 5-lipoxygenase inhibitor, Abbott-79175, in beagle dogs

Abstract

The pulmonary bioavailability and absorption characteristics of two aerosol suspensions of a potent 5-lipoxygenase inhibitor, Abbott-79175, containing different dispersants (formulations B and C) were investigated using an intravenous (i.v.) formulation of the drug as a reference. A reverse-phase HPLC assay was used to analyze drug concentrations in serial blood samples taken after drug administration to groups of nine tracheostomized dogs. Both formulations demonstrated fast onset of drug absorption from the lung which lasted for about 9 h. Data stripping yielded absolute bioavailabilities of 57.8 (± 25.7) and 68.4 (± 22.8)% for formulations B and C, respectively. Analysis of variance (ANOVA) yielded sources of variation in each data set thus providing a means for comparisons. Moment analysis and deconvolution (PCDCON and RSTRIP) using i.v. data as the unit impulse response enabled estimation of drug absorption from the formulations for each animal. The apparent absorption of aerosolized drug from the lungs was found to fit first-order kinetics ( k 1 = 0.083 and 0.093 h −1 for formulations B and C, respectively). The results also suggested involvement of particle dissolution phenomenon as potential rate-limiting step in the absorption process (e.g., cube-root model: k 1 3 = 0.023 and 0.026 h −1 for formulations B and C, respectively). Hence, it appears that particle dissolution as well as membrane transport may be rate determining processes in the absorption of Abbott-79175 from the airways.