Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Am Hubland, 97074 Würzburg, Germany.
Pulm Pharmacol Ther. 2012 Feb;25(1):124-34. doi: 10.1016/j.pupt.2011.12.009. Epub 2012 Jan 5.
The aim of the present investigation was to compare the pulmonary absorption of the novel long-acting β(2)-agonist GW597901 with salbutamol and to determine the influence of an induced bronchoconstriction on the pharmacokinetics of the compounds using a human lung reperfusion model.
In an initial study with six lung perfusions the pharmacokinetic properties of the β(2)-agonists were determined. We then investigated the influence of an induced bronchoconstriction on the pulmonary absorption in six lung lobes for each drug. Therefore, methacholine (MCh) challenge agent was nebulised prior to administration of the β(2)-agonists.
As expected, the extent of pulmonary absorption of salbutamol into the perfusate was more pronounced than for the more lipophilic GW597901. Although the observed differences were not statistically significant they were further supported by analysis of tissue concentrations. In contrast, we observed a statistically significant influence of the bronchoprovocation with MCh on the pulmonary absorption of both β(2)-agonists, but this effect was not limited to a successfully induced bronchoconstriction. A prominent decline of salbutamol distribution into perfusion fluid was also observed when the organic cation transporter substrate carnitine was nebulised prior to the bronchodilator.
Nebulised methacholine had a significant influence on the pharmacokinetics of bronchodilators. Since we observed this effect independently of a successfully induced bronchoconstriction and also after nebulisation of carnitine we suggest a significant delay of pulmonary absorption of inhaled salbutamol and GW597901 due to competition for a cation/carnitine drug transporter, most likely OCTN2.
本研究旨在比较新型长效β(2)-激动剂 GW597901 与沙丁胺醇的肺部吸收，并利用人体肺再灌注模型，确定支气管收缩对化合物药代动力学的影响。
在最初的 6 个肺灌注研究中，确定了β(2)-激动剂的药代动力学特性。然后，我们研究了在每个药物的 6 个肺叶中，诱导的支气管收缩对肺部吸收的影响。因此，在给予β(2)-激动剂之前，用乙酰甲胆碱（MCh）激发剂进行雾化。
正如预期的那样，沙丁胺醇在灌注液中的肺部吸收程度比脂溶性更强的 GW597901 更为明显。尽管观察到的差异没有统计学意义，但通过组织浓度分析进一步支持了这一结果。相比之下，我们观察到 MCh 支气管激发对两种β(2)-激动剂的肺部吸收都有统计学意义的影响，但这种影响不仅限于成功诱导的支气管收缩。当有机阳离子转运体底物肉碱在支气管扩张剂之前进行雾化时，也观察到沙丁胺醇在灌注液中的分布明显下降。
雾化的乙酰甲胆碱对支气管扩张剂的药代动力学有显著影响。由于我们观察到这种效应独立于成功诱导的支气管收缩，并且在雾化肉碱后也观察到这种效应，我们建议由于竞争阳离子/肉碱药物转运体（可能是 OCTN2），吸入沙丁胺醇和 GW597901 的肺部吸收明显延迟。
