Comparison of Oral, Intranasal and Aerosol Administration of Amiodarone in Rats as a Model of Pulmonary Phospholipidosis
Aateka Patel,
Ewelina Hoffman,
Doug Ball,
Jan Klapwijk,
Rory T. Steven,
Alex Dexter,
Josephine Bunch,
Daniel Baker,
Darragh Murnane,
Victoria Hutter,
Clive Page,
Lea Ann Dailey,
Ben Forbes
Affiliations
Aateka Patel
Sackler Institute of Pulmonary Pharmacology, Faculty of Life Sciences & Medicine, Franklin-Wilkins Building, King’s College London, 150 Stamford Street, London SE1 9NH, UK
Ewelina Hoffman
Centre for Topical Drug Delivery and Toxicology, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Herts AL10 9AB, UK
Doug Ball
Allergic Inflammation Discovery Performance Unit, GlaxoSmithKline, Gunnelswood Road, Stevenage, Herts SG1 2NY, UK
Jan Klapwijk
Translational Medicine and Comparative Pathobiology, GlaxoSmithKline, Park Road, Ware, Hertfordshire SG12 0DP, UK
Rory T. Steven
National Physical Laboratory, Teddington, London TW11 0LW, UK
Alex Dexter
National Physical Laboratory, Teddington, London TW11 0LW, UK
Josephine Bunch
National Physical Laboratory, Teddington, London TW11 0LW, UK
Daniel Baker
Centre for Topical Drug Delivery and Toxicology, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Herts AL10 9AB, UK
Darragh Murnane
Centre for Topical Drug Delivery and Toxicology, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Herts AL10 9AB, UK
Victoria Hutter
Centre for Topical Drug Delivery and Toxicology, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Herts AL10 9AB, UK
Clive Page
Sackler Institute of Pulmonary Pharmacology, Faculty of Life Sciences & Medicine, Franklin-Wilkins Building, King’s College London, 150 Stamford Street, London SE1 9NH, UK
Lea Ann Dailey
Institute of Pharmaceutical Technology and Biopharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06108 Halle (Saale), Germany
Ben Forbes
Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, King’s College London, 150 Stamford Street, London SE1 9NH, UK
‘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.
