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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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 di_erential 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.

Original languageEnglish
Article number345
JournalPharmaceutics
Volume11
Issue number7
DOIs
Publication statusPublished - 17 Jul 2019

Keywords

  • Amiodarone
  • Di-22:6 bis-monoacylglycerol
  • Foamy alveolar macrophages
  • High content analysis
  • Mass spectrometry imaging
  • Phospholipidosis

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