A 3D Model of the\nHuman Lung Airway for Evaluating\nPermeability of Inhaled Drugs

Current in vitro cell-based methods, relying on single\ncell types,\nhave structural and functional limitations in determining lung drug\npermeability, which is a contributing factor affecting both local\nand systemic drug levels. To address this issue, we investigated a\n3D human lung airway model generated using a cell culture insert,\nwherein primary human lung epithelial and endothelial cells were cocultured\nat an air–liquid interface (ALI). To ensure that the cell culture\nmimics the physiological and functional characteristics of airway\ntissue, the model was characterized by evaluating several parameters\nsuch as cellular confluency, ciliation, tight junctions, mucus-layer\nformation, transepithelial electrical resistance, and barrier function\nthrough assaying fluorescein isothiocyanate-dextran permeability.\nTo understand how the characterized ALI quality attributes influenced\nthe absorption of inhaled drugs through the epithelial-endothelial\nbarrier, we measured the permeability and epithelial intracellular\nconcentrations of albuterol sulfate (AL), formoterol fumarate (FO),\nand fluticasone furoate (FL). The presented characterization results\noverall demonstrate that this culture platform mimicked the airway-specific\nstructure and barrier function. An apparent permeability (<i>P</i><sub>app</sub>) of 5.7 × 10<sup>–6</sup> cm/s\nand an intracellular concentration below 1% were quantified for AL\nover 3 h. The <i>P</i><sub>app</sub> of FO was 8.5 ×\n10<sup>–6</sup> cm/s, with an intracellular concentration of\n3.8%. Due to its high lipophilicity, FL showed a higher intracellular\nconcentration (17.4%) compared to AL and FO, but also a 73.1% loss\nof the compound over 3 h due to nonspecific binding, with a <i>P</i><sub>app</sub> as low as 1.3 × 10<sup>–7</sup> cm/s. While the model exhibited physiologically relevant properties,\nits utility in estimating the permeability of inhaled drugs may be\ndrug-specific, warranting further optimization and study.