Solute Absorption from the Airways of the Isolated Rat Lung. I. The Use of Absorption Data to Quantify Drug Dissolution or Release in the Respiratory Tract

Abstract

Coprecipitates of fluorescein and magnesium hydroxide demonstrate delayed absorption relative to fluorescein solutions when administered to the airways of the isolated perfused rat lung (IPRL). Perfusate concentration vs time profiles showed that dissolution and not epithelial permeability was the rate-controlling factor in the airway-to-perfusate transfer process. A simple data deconvolution method was developed to determine the fluorescein release from the microparticulate coprecipitates in the airways. The deconvolution technique is generally applicable and provides values for undissolved solute remaining in the airways as a function of time provided that (a) significant binding and/or metabolism does not occur, (b) absorption from solution is apparent first order, and (c) all solid or dissolved material reaching perfused regions is absorbed within the lifetime of the preparation. Increased release rates of fluorescein occurred from precipitates containing greater starting concentrations of the dye. Dissolution profiles were similar to those that occur for log-normally distributed powders. The analysis of two unusual time profiles implied that the regional distribution of solid and dissolved material, between perfused areas and nonperfused areas, could be nonhomogeneous despite the use of a standardized dosing technique. The studies describe a method of using the IPRL with the potential to screen aerosol formulations for extended dissolution in the respiratory tract.