Himstedt Anneke, Braun Clemens, Wicha Sebastian Georg, Borghardt Jens Markus
Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, 20146 Hamburg, Germany.
Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany.
Pharmaceutics. 2020 Apr 29;12(5):408. doi: 10.3390/pharmaceutics12050408.
Increasing affinity to lung tissue is an important strategy to achieve pulmonary retention and to prolong the duration of effect in the lung. As the lung is a very heterogeneous organ, differences in structure and blood flow may influence local pulmonary disposition. Here, a novel lung preparation technique was employed to investigate regional lung distribution of four drugs (salmeterol, fluticasone propionate, linezolid, and indomethacin) after intravenous administration in rats. A semi-mechanistic model was used to describe the observed drug concentrations in the trachea, bronchi, and the alveolar parenchyma based on tissue specific affinities (K) and blood flows. The model-based analysis was able to explain the pulmonary pharmacokinetics (PK) of the two neutral and one basic model drugs, suggesting up to six-fold differences in K between trachea and alveolar parenchyma for salmeterol. Applying the same principles, it was not possible to predict the pulmonary PK of indomethacin, indicating that acidic drugs might show different pulmonary PK characteristics. The separate estimates for local K, tracheal and bronchial blood flow were reported for the first time. This work highlights the importance of lung physiology- and drug-specific parameters for regional pulmonary tissue retention. Its understanding is key to optimize inhaled drugs for lung diseases.
增强对肺组织的亲和力是实现肺部滞留并延长肺部作用持续时间的重要策略。由于肺是一个非常异质性的器官，结构和血流的差异可能会影响局部肺部处置。在此，采用了一种新型的肺制备技术来研究大鼠静脉注射四种药物（沙美特罗、丙酸氟替卡松、利奈唑胺和吲哚美辛）后的区域肺分布。基于组织特异性亲和力（K）和血流，使用半机制模型来描述在气管、支气管和肺泡实质中观察到的药物浓度。基于模型的分析能够解释两种中性和一种碱性模型药物的肺部药代动力学（PK），表明沙美特罗在气管和肺泡实质之间的K值差异高达六倍。应用相同的原理，无法预测吲哚美辛的肺部PK，这表明酸性药物可能表现出不同的肺部PK特征。首次报告了局部K、气管和支气管血流的单独估计值。这项工作突出了肺生理学和药物特异性参数对区域肺组织滞留的重要性。对其的理解是优化用于肺部疾病的吸入药物的关键。
