Bäckström Erica, Boger Elin, Lundqvist Anders, Hammarlund-Udenaes Margareta, Fridén Markus
Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden; Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal 431 83, Sweden.
Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal 431 83, Sweden; School of Engineering, University of Warwick, Coventry CV4 7AL, United Kingdom.
J Pharm Sci. 2016 Nov;105(11):3432-3439. doi: 10.1016/j.xphs.2016.08.014. Epub 2016 Sep 23.
Modulating and optimizing the local pharmacokinetics of inhaled drugs by chemical design or formulation is challenged by the lack of predictive in vitro systems and in vivo techniques providing a detailed description of drug location in the lung. The present study investigated whether a new experimental setup of freshly prepared agarose-filled lung slices can be used to estimate lung retention in vitro, by comparing with in vivo lung retention after intratracheal instillation. Slices preloaded with inhaled β-adrenergic compounds (salbutamol, formoterol, salmeterol, indacaterol or AZD3199) were incubated in a large volume of buffer (w/wo monensin to assess the role of lysosomal trapping), and the amount remaining in slices at different time points was determined with liquid chromatography-tandem mass spectrometry. The in vitro lung retention closely matched the in vivo lung retention (half-lives within 3-fold for 4/5 compounds), and monensin shortened the half-lives for all compounds. The results suggest that freshly prepared rat lungs slices can be used to predict lung retention and that slow kinetics of lysosomal trapping is a key mechanism by which retention in the lung and the effect duration of inhaled β-adrenergic bronchodilators are prolonged.
通过化学设计或制剂来调节和优化吸入药物的局部药代动力学面临挑战，因为缺乏能够详细描述药物在肺中位置的预测性体外系统和体内技术。本研究通过将新鲜制备的琼脂糖填充肺切片的新实验装置与气管内滴注后的体内肺滞留情况进行比较，研究其是否可用于体外估计肺滞留。预先加载吸入性β-肾上腺素能化合物（沙丁胺醇、福莫特罗、沙美特罗、茚达特罗或AZD3199）的切片在大量缓冲液中孵育（添加/不添加莫能菌素以评估溶酶体捕获的作用），并通过液相色谱-串联质谱法测定不同时间点切片中剩余的量。体外肺滞留与体内肺滞留密切匹配（4/5种化合物的半衰期在3倍以内），莫能菌素缩短了所有化合物的半衰期。结果表明新鲜制备的大鼠肺切片可用于预测肺滞留，溶酶体捕获的缓慢动力学是延长吸入性β-肾上腺素能支气管扩张剂在肺中的滞留和作用持续时间的关键机制。
