The development of new inhaled medicines for the treatment of airway disease is being held back by the lack of understanding of how the airways respond to inhaled particulate therapies. A highly vacuolated or ‘foamy’ alveolar macrophage response is often observed in the lungs of rats when dosed with inhaled particulate candidate drugs which prevents their progression in drug discovery on the grounds of safety, despite not fully understanding if these responses are adverse in humans. It is currently unknown if these alveolar macrophages responses are mediated by the soluble or particulate fraction of these compounds in the lung. The aim of this study was to develop methodology to test if cellular responses to poorly aqueous soluble compounds were caused by the pharmacology of the drug and the soluble fraction entering the cells, or by physicochemical interaction of the insoluble particulate material with the alveolar macrophages. Amiodarone was selected as a model drug as it is a cationic amphiphilic compound established for inducing phospholipidosis in the airways. Concentrations between 1-100 μM amiodarone were prepared and either left unfiltered or filtered through a 0.2 μm filter. Solubility studies indicated that 8% of the 100 μM amiodarone preparation was not solubilised, however no significant differences (p>0.05) were observed for viability and phospholipidosis responses in the rat alveolar macrophage cell line, NR8383. Preliminary results indicate that the pharmacological action of amiodarone in its solubilised form primarily mediates alveolar toxicity rather than the interactions of the insoluble particulates with the cells. It is anticipated that similar studies will aid a better understanding of the pathophysiology of airway immune responses to characterise whether the soluble or insoluble fraction of poorly aqueous soluble inhaled drug compounds is responsible for adverse alveolar responses. This will help inform the safety assessment process for new inhaled medicines in drug discovery.