The isolated perfused lung: a bridge between in vitro and in vivo studies of inhaled medicinal products

Understanding the complex relationship between drug deposition, pulmonary pharmacokinetics, and clinical efficacy is essential to developing effective inhaled therapies. Harnessing formulation physicochemical properties can improve aerodynamic properties and enhance lung retention, yet predictive in vitro and in silico models remain essential for advanced formulation development. A range of in vitro lung epithelial models has been explored to study transepithelial transport. However, these systems often lack physiological complexity. Advanced platforms such as organoids and lung-on-a-chip models attempt to replicate the structural and mechanical features of the lung, though they face limitations in airflow simulation, aerosol characterization, and operational complexity. Consequently, preclinical in vivo rodent studies continue to play a key role due to their ability to capture systemic interactions. However, several challenges remain, particularly in isolating lung-specific pharmacokinetics. The review focuses on the use of the isolated perfused rat lung (IPL), an ex vivo model that emerged as a valuable tool allowing for the direct measurement of pulmonary absorption while minimizing systemic confounding variables. This model supports accurate control of lung dosing and enables evaluation of local metabolism, clearance, and drug retention. The review outlines IPL setup, applications, and its role in supporting the 3Rs principles (Replace, Reduce, Refine) in animal testing. As an innovative tool, IPL enhances the understanding of pulmonary drug behaviour and holds promise for improving inhaled drug development through more ethical and precise preclinical research.