Abstract
‘Foamy’ alveolar macrophages (FAM) observed in nonclinical toxicology studies during inhaled drug development may indicate drug-induced phospholipidosis, but can also derive from adaptive non-adverse mechanisms. Orally administered amiodarone is currently used as a model of pulmonary phospholipidosis and it was hypothesized that aerosol administration would produce phospholipidosis-induced FAM that could be characterized and used in comparative inhalation toxicology. Han-Wistar rats were given amiodarone via (1) intranasal administration (6.25 mg/kg) on two days, (2) aerosol administration (3 mg/kg) on two days, (3) aerosol administration (10 mg/kg) followed by three days of 30 mg/kg or (4) oral administration (100 mg/kg) for 7 days. Alveolar macrophages in bronchoalveolar lavage were evaluated by differential cell counting and high content fluorescence imaging. Histopathology and mass-spectrometry imaging (MSI) were performed on lung slices. The higher dose aerosolised amiodarone caused transient pulmonary inflammation (p < 0.05), but only oral amiodarone resulted in FAM (p < 0.001). MSI of the lungs of orally treated rats revealed a homogenous distribution of amiodarone and a putative phospholipidosis marker, di-22:6 bis-monoacylglycerol, throughout lung tissue whereas aerosol administration resulted in localization of both compounds around the airway lumen. Thus, unlike oral administration, aerosolised amiodarone failed to produce the expected FAM responses.
Highlights
Inhaled therapies for asthma were first developed in the 1950s and remain the preferred route of administration for treating the disease [1]
All control groups showed outcomes in line with values reported in literature [19,29,30], i.e., total cell counts were normal, and no inflammatory cells were present in the bronchoalveolar lavage (BAL) cellular fraction (Figure 1)
cationic amphiphilic drug (CAD) administered systemically have foamy alveolar macrophages (FAM) distributed throughout the lungs, whereas, when CADs are inhaled FAMs are predominantly localised at the bronchoalveolar junction and the site of deposition [38]
Summary
Inhaled therapies for asthma were first developed in the 1950s and remain the preferred route of administration for treating the disease [1]. There have been few new classes of drugs licensed during the past 50 years, with many that perform well in pre-clinical animal studies failing in pre-clinical development owing to a lack of safety and/or efficacy in humans [2]. Failure to translate promising drug effects from pre-clinical assays and animal studies to humans has led to questions regarding the relevance of current pre-clinical models, and a demand for more predictive in vivo and in vitro tools. One of the difficulties in non-clinical assessment of inhaled drug safety is uncertainties around the alveolar macrophage (AM) response in animals and its relevance to safety in the clinic [2]. A typical finding in toxicity studies with inhaled formulations of new drugs is the induction of foamy alveolar macrophages (FAM) which may or may not be indicative of subsequent adverse events.
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