Short inhalation exposures of the isolated and perfused rat lung to respirable dry particle aerosols;: The detailed pharmacokinetics of budesonide, formoterol, and terbutaline
Short inhalation exposures of the isolated and perfused rat lung to respirable dry particle aerosols;: The detailed pharmacokinetics of budesonide, formoterol, and terbutaline
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DOI：
10.1089/jamp.2007.0654
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发表时间：
2008-06-01
影响因子：
3.4
通讯作者：
Gerde, Per
中科院分区：
文献类型：
--
作者：
Ewing, Per;Eirefelt, Stefan J.;Gerde, Per
人们越来越关注使用肺作为药物局部和全身给药的进入途径。然而，由于在临床前环境中缺少足够的技术，很少有研究者讨论了短时间吸入暴露于高浓度干粉气雾剂后药物在肺中的详细分布。需要新的方法来探索短期吸入暴露后药物的处置，从而模拟未来的临床应用。我们的目的是研究临床上用于治疗支气管哮喘的布地奈德、福莫特罗和特布他林的肺处置。使用最近开发的DustGun气溶胶技术，我们暴露于吸入约1分钟的隔离和灌注大鼠肺（IPL）的可吸入干颗粒气溶胶的三种药物在高浓度。典型的气溶胶浓度为1 μ/mL，测试物质的粒度分布随MMAD变化，范围为2.3至5.3 μ m。以单次通过模式灌注IPL，并在暴露后80 min内重复采集灌注液样本。使用LC-MS/MS测量灌流液和肺提取物中的药物浓度。通过将灌流液中收集的药物量与80分钟时从组织中提取的药物量相加来确定沉积剂量。布地奈德、富马酸福莫特罗和硫酸特布他林的沉积量分别为23 +/- 17，36 +/- 8，和60 ± 3.2 μ g（平均值± SD，n = 3）。在灌注期结束时，布地奈德、福莫特罗和特布他林在肺组织中的滞留分别为0.19 +/- 0.05、0.19 +/- 0.06和0.04 +/- 0.01（平均SD，n = 3），表示为沉积剂量的分数。每次短时间吸入暴露于高浓度气雾剂消耗1-3 mg粉末。因此，该系统对于在药物发现/开发中获得吸入化合物的详细药代动力学表征特别有用。
There is an increasing interest in using the lung as a route of entry for both local and systemic administration of drugs. However, because adequate technologies have been missing in the preclinical setting, few investigators have addressed the detailed disposition of drugs in the lung following short inhalation exposures to highly concentrated dry powder aerosols. New methods are needed to explore the disposition of drugs after short inhalation exposures, thus mimicking a future clinical use. Our aim was to study the pulmonary disposition of budesonide, formoterol, and terbutaline, which are clinically used for the treatment of bronchial asthma. Using the recently developed DustGun aerosol technology, we exposed by inhalation for approximately 1 min the isolated and perfused rat lung (IPL) to respirable dry particle aerosols of the three drugs at high concentrations. The typical aerosol concentration was 1 mu/mL, and the particle size distribution of the tested substances varied with a MMAD ranging from 2.3 to 5.3 mu m. The IPL was perfused in single pass mode and repeated samples of the perfusate were taken for up to 80 min postexposure. The concentration of drug in perfusate and in lung extracts was measured using LC-MS/MS. The deposited dose was determined by adding the amounts of drug collected in perfusate to the amount extracted from the tissues at 80 min. Deposited amounts of budesonide, formoterol fumarate, and terbutaline sulphate were 23 +/- 17, 36 +/- 8, and 60 +/- 3.2 mu g (mean +/- SD, n = 3), respectively. Retention in lung tissues at the end of the perfusion period expressed as fraction of deposited dose was 0.19 +/- 0.05, 0.19 +/- 0.06, and 0.04 +/- 0.01 (mean SD, n = 3) for budesonide, formoterol, and terbutaline, respectively. Each short inhalation exposure to the highly concentrated aerosols consumed 1-3 mg powder. Hence, this system can be particularly useful for obtaining a detailed pharmacokinetic characterization of inhaled compounds in drug discovery/development.