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Open AccessArticle

Comparison of Oral, Intranasal and Aerosol Administration of Amiodarone in Rats as a Model of Pulmonary Phospholipidosis

1
Sackler Institute of Pulmonary Pharmacology, Faculty of Life Sciences & Medicine, Franklin-Wilkins Building, King’s College London, 150 Stamford Street, London SE1 9NH, UK
2
Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, King’s College London, 150 Stamford Street, London SE1 9NH, UK
3
Centre for Topical Drug Delivery and Toxicology, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Herts AL10 9AB, UK
4
Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Pharmacy Faculty, Medical University of Lodz, 90-151 Lodz, Poland
5
Allergic Inflammation Discovery Performance Unit, GlaxoSmithKline, Gunnelswood Road, Stevenage, Herts SG1 2NY, UK
6
Translational Medicine and Comparative Pathobiology, GlaxoSmithKline, Park Road, Ware, Hertfordshire SG12 0DP, UK
7
National Physical Laboratory, Teddington, London TW11 0LW, UK
8
Institute of Pharmaceutical Technology and Biopharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06108 Halle (Saale), Germany
*
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(7), 345; https://doi.org/10.3390/pharmaceutics11070345
Received: 31 May 2019 / Revised: 10 July 2019 / Accepted: 11 July 2019 / Published: 17 July 2019
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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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. View Full-Text
Keywords: phospholipidosis; amiodarone; foamy alveolar macrophages; di-22:6 bis-monoacylglycerol; mass spectrometry imaging; high content analysis phospholipidosis; amiodarone; foamy alveolar macrophages; di-22:6 bis-monoacylglycerol; mass spectrometry imaging; high content analysis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Patel, A.; Hoffman, E.; Ball, D.; Klapwijk, J.; Steven, R.T.; Dexter, A.; Bunch, J.; Baker, D.; Murnane, D.; Hutter, V.; Page, C.; Dailey, L.A.; Forbes, B. Comparison of Oral, Intranasal and Aerosol Administration of Amiodarone in Rats as a Model of Pulmonary Phospholipidosis. Pharmaceutics 2019, 11, 345.

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