Uncovering the regional localization of inhaled salmeterol retention in the lung

Drug Deliv. 2018 Nov;25(1):838-845. doi: 10.1080/10717544.2018.1455762.

Abstract

Treatment of respiratory disease with a drug delivered via inhalation is generally held as being beneficial as it provides direct access to the lung target site with a minimum systemic exposure. There is however only limited information of the regional localization of drug retention following inhalation. The aim of this study was to investigate the regional and histological localization of salmeterol retention in the lungs after inhalation and to compare it to systemic administration. Lung distribution of salmeterol delivered to rats via nebulization or intravenous (IV) injection was analyzed with high-resolution mass spectrometry imaging (MSI). Salmeterol was widely distributed in the entire section at 5 min after inhalation, by 15 min it was preferentially retained in bronchial tissue. Via a novel dual-isotope study, where salmeterol was delivered via inhalation and d3-salmeterol via IV to the same rat, could the effective gain in drug concentration associated with inhaled delivery relative to IV, expressed as a site-specific lung targeting factor, was 5-, 31-, and 45-fold for the alveolar region, bronchial sub-epithelium and epithelium, respectively. We anticipate that this MSI-based framework for quantifying regional and histological lung targeting by inhalation will accelerate discovery and development of local and more precise treatments of respiratory disease.

Keywords: Pulmonary distribution; inhalation; lung retention; mass spectrometry imaging; pharmacokinetics.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Inhalation
  • Adrenergic beta-2 Receptor Agonists / administration & dosage*
  • Adrenergic beta-2 Receptor Agonists / metabolism
  • Adrenergic beta-2 Receptor Agonists / pharmacokinetics
  • Adrenergic beta-2 Receptor Agonists / pharmacology
  • Animals
  • Bronchi / cytology
  • Bronchi / diagnostic imaging
  • Bronchi / drug effects
  • Bronchi / metabolism*
  • Bronchodilator Agents / administration & dosage*
  • Bronchodilator Agents / metabolism
  • Bronchodilator Agents / pharmacokinetics
  • Bronchodilator Agents / pharmacology
  • Cluster Analysis
  • Deuterium
  • Injections, Intravenous
  • Lung / cytology
  • Lung / diagnostic imaging
  • Lung / drug effects
  • Lung / metabolism*
  • Male
  • Mass Spectrometry
  • Molecular Imaging
  • Pharmaceutical Vehicles / chemistry
  • Phosphatidylethanolamines / chemistry
  • Polyethylene Glycols / chemistry
  • Polysorbates / chemistry
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / diagnostic imaging
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism*
  • Rats, Wistar
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / diagnostic imaging
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / metabolism*
  • Respiratory Tract Absorption
  • Salmeterol Xinafoate / administration & dosage*
  • Salmeterol Xinafoate / metabolism
  • Salmeterol Xinafoate / pharmacokinetics
  • Salmeterol Xinafoate / pharmacology
  • Tissue Distribution

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Bronchodilator Agents
  • Pharmaceutical Vehicles
  • Phosphatidylethanolamines
  • Polysorbates
  • 1,2-dipalmitoyl-3-phosphatidylethanolamine
  • Polyethylene Glycols
  • Salmeterol Xinafoate
  • monomethoxypolyethylene glycol
  • Deuterium

Grants and funding

This study was supported by AstraZeneca. PE and AN were supported by the Swedish Research Council (Natural and Engineering Science #2014-6215), the Swedish Foundation for Strategic Research #RIF14-0078, and a Science for Life Laboratory (SciLifeLab) grant.