Ex Vivo Isolated Perfused Rat Lung: A Valuable Tool for assessing the Pulmonary Absorption of Inhaled Drugs

This study investigated the potential of the ex vivo isolated perfused rat lung (IPL) model to predict lung absorption of inhaled drugs. Compared to in vitro methods, IPL offers a more realistic environment by mimicking key aspects of lung function and maintaining the physiological tissue barriers. The research was focused on a poorly water-soluble compound in pharmaceutical development (compound A) delivered in three forms: free-base as powder (powder 1), compound salt as powder (powder 2) and free base as nanosuspension. IPL technique allowed for controlled administration and frequent sampling of the perfusate to assess drug absorption. This approach aimed at reducing the number of animals needed for in vivo studies, adhering to the 3Rs principles. IPL experiments compared the pulmonary absorption profiles obtained with the three formulations and then with the plasma profiles obtained in in vivo studies in rats. Results showed a high degree of concordance between the ex vivo and in vivo pharmacokinetic profiles for all formulations, despite the use of different devices for administering powders in ex vivo and in vivo settings. Notably, the nanosuspension achieved a well-defined peak concentration with early Tmax, while the powder formulations reached a plateau few minutes after administration, likely due to the slower dissolution. Overall, this study demonstrates the valuable role of the IPL model in analysing and possibly predicting the pharmacokinetics of inhaled drugs, particularly for poorly water-soluble compounds. The ability to reduce animal usage and provide more frequent sampling points makes this technique a promising tool for pre-clinical drug development.