a Drug Metabolism and Pharmacokinetics, Respiratory, Inflammation and Autoimmunity IMED Biotech Unit , AstraZeneca , Gothenburg , Sweden.
b Pathology Sciences, Drug Safety & Metabolism IMED Biotech Unit , AstraZeneca , Cambridge , UK.
Drug Deliv. 2018 Nov;25(1):838-845. doi: 10.1080/10717544.2018.1455762.
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 d-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.
通过吸入给药治疗呼吸系统疾病通常被认为是有益的，因为它可以通过最小的全身暴露直接到达肺部靶位。然而，关于吸入后药物在肺部的局部定位的信息非常有限。本研究旨在通过高分辨率质谱成像（MSI）研究吸入沙美特罗后其在肺部的局部和组织学定位，并将其与全身给药进行比较。通过对通过雾化或静脉（IV）注射给予大鼠的沙美特罗进行分析，发现吸入后 5 分钟沙美特罗在整个切片中广泛分布，15 分钟后它优先保留在支气管组织中。通过一项新的双同位素研究，即通过吸入给予沙美特罗，同时通过 IV 给予 d-沙美特罗，与 IV 相比，吸入给药与肺泡区域、支气管亚上皮和上皮分别获得 5 倍、31 倍和 45 倍的药物浓度有效增益，可表示为局部肺靶向因子。我们预计，这种基于 MSI 的框架将加速发现和开发针对呼吸系统疾病的局部和更精确的治疗方法。
