Uncovering the regional localization of inhaled salmeterol retention in the lung

Drug Delivery

Anna Nilsson¹  Per Andrén¹  Erica Bäckström²  Britt-Marie Fihn²  Markus Fridén³  Gregory Hamm⁴  Richard J. A. Goodwin⁴  Nicole Strittmatter⁴ 

[1] Biomolecular Mass Spectrometry Imaging, National Resource for MSI, Science for Life Laboratory, Dept. of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden;Drug Metabolism and Pharmacokinetics, Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden;Drug Metabolism and Pharmacokinetics, Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden;Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Swede;Pathology Sciences, Drug Safety & Metabolism IMED Biotech Unit, AstraZeneca, Cambridge, UK;

关键词: Pulmonary distribution;    lung retention;    mass spectrometry imaging;    pharmacokinetics;    inhalation;   

DOI  :  10.1080/10717544.2018.1455762

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY