Investigation into pulmonary absorption using a combination of the ex vivo model of isolated perfused rat lungs and a simple PK model
Ex vivo models are attractive tools for non-clinical testing of new drug candidates and formulations as well as for safety assessment of chemicals due to their proximity to the in vivo situation and their potential to reduce and refine in vivo tests. The aim was to investigate the applicability of IPLs as a model for pulmonary absorption studies. The ex vivo model of Isolated Perfused Rat Lungs (IPLs) has been established as a tool for investigations into the systemic uptake of inhaled substances through the lung. Lungs from rats are ventilated and perfused with a physiologic buffer solution. Respiratory parameters, such as tidal volume, dynamic compliance as well as pulmonary arterial pressure are measured on-line for monitoring of pulmonary viability. For investigations into mass transfer processes through the lung, IPLs are exposed to rat-respirable aerosols. Subsequently, the concentration profile of the substance is analyzed in the perfusate. For translation of the PK data obtained in the experiments into a transfer velocity (permeability coefficient), a simple physiological 3-compartment-model (lung lining fluid, tissue, blood), simulating the systemic uptake in the IPL, was applied. Relevant physiological and morphological data were gathered from literature. Analyses of perfusate concentration profiles after exposure of IPLs to respirable aerosols of small molecule substances allowed for a qualitative ranking of the systemic uptake, which is in good agreement with data from human studies (small molecule). The transfer velocity determined using the simple PK-model was 2 - 3 x 10E-06 cm/s, i.e. a rapid absorption was observed. The current investigations demonstrate the high potential of Isolated Perfused Rat Lungs as a tool for investigation of the systemic uptake of inhaled substances with rapid absorption. The kinetic data derived from this model might serve as input parameters for PBPK modelling. In addition, in the context of absorption studies, the IPL model might be useful for further mechanistic investigations, such as the elucidation of transport mechanisms through the alveolarepithelial membrane. To summarize, the model of the Isolated Perfused Lungs is strongly assumed to be suitable for studies into pulmonary absorption of inhaled chemicals or pharmaceuticals and therefore also contributes well to the 3R principles.