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首页> 外文期刊>Advanced drug delivery reviews >In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery.
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In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery.

机译：在体内，体外和离体模型中评估肺吸收和全身治疗用吸入性治疗药物的处置。

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Despite the interest in systemic delivery of therapeutic molecules including macromolecular proteins and peptides via the lung, the accurate assessment of their pulmonary biopharmaceutics is a challenging experimental task. This article reviews in vivo, in vitro and ex vivo models currently available for studying lung absorption and disposition for inhaled therapeutic molecules. The general methodologies are discussed with recent advances, current challenges and perspectives, especially in the context of their use in systemic pulmonary delivery research. In vivo approaches in small rodents continue to be the mainstay of assessment by virtue of the acquisition of direct pharmacokinetic data, more meaningful when attention is given to reproducible dosing and control of lung-regional distribution through use of more sophisticated lung-dosing methods, such as forced instillation, microspray, nebulization and aerosol puff. A variety of in vitro lung epithelial cell lines models and primary cultured alveolarepithelial (AE) cells when grown to monolayer status offer new opportunity to clarify the more detailed kinetics and mechanisms of transepithelial drug transport. While continuous cell lines, Calu-3 and 16HBE14o-, show potential, primary cultured AE cell models from rat and human origins may be of greater use, by virtue of their universally tight intercellular junctions that discriminate the transport kinetics of different therapeutic entities. Nevertheless, the relevance of using these reconstructed barriers to represent complex disposition of intact lung may still be debatable. Meanwhile, the intermediate ex vivo model of the isolated perfused lung (IPL) appears to resolve deficiencies of these in vivo and in vitro models. While controlling lung-regional distributions, the preparation alongside a novel kinetic modeling analysis enables separate determinations of kinetic descriptors for lung absorption and non-absorptive clearances, i.e., mucociliary clearance, phagocytosis and/or metabolism. This ex vivo model has been shown to be kinetically predictive of in vivo, with respect to macromolecular disposition, despite limitations concerning short viable periods of 2-3 h and likely absence of tracheobronchial circulation. Given the advantages and disadvantages of each model, scientists must make appropriate selection and timely exploitation of the best model at each stage of the research and development program, affording efficient progress toward clinical trials for future inhaled therapeutic entities for systemic delivery.
机译：尽管有兴趣通过肺系统地输送包括大分子蛋白质和肽在内的治疗分子，但准确评估其肺部生物药物仍然是一项艰巨的实验任务。本文回顾了目前可用于研究吸入性治疗分子的肺吸收和处置的体内，体外和离体模型。讨论了一般方法的最新进展，当前的挑战和观点，尤其是在系统肺递送研究中使用它们的背景下。由于直接获得药代动力学数据，小啮齿动物的体内方法仍然是评估的主要手段，当注意通过使用更复杂的肺部给药方法（例如，可重复使用的剂量）和控制肺区域分布时，这种方法就更加有意义。如强制滴注，微喷雾，雾化和气雾剂。当生长到单层状态时，多种体外肺上皮细胞系模型和原代培养的肺泡上皮（AE）细胞提供了新的机会来阐明跨上皮药物转运的更详细的动力学和机制。尽管连续细胞系Calu-3和16HBE140o具有潜力，但由于它们普遍具有紧密的细胞间连接，可以区分不同治疗实体的运输动力学，因此来自大鼠和人类的原代培养的AE细胞模型可能会得到更大的利用。然而，使用这些重建的屏障来代表完整肺的复杂处置的相关性仍有待商bat。同时，分离的灌注肺（IPL）的中间离体模型似乎可以解决这些体内和体外模型的缺陷。在控制肺区域分布的同时，该制剂与新颖的动力学模型分析一起使得能够分别确定肺吸收和非吸收性清除（即，粘膜纤毛清除，吞噬作用和/或代谢）的动力学描述符。尽管存在关于2-3小时的短生存期的限制以及可能不存在气管支气管循环的限制，但是已经证明该离体模型相对于大分子布置是体内动力学预测的。鉴于每种模型的优缺点，科学家必须在研究和开发计划的每个阶段做出适当的选择并及时开发最佳模型，从而为将来进行系统递送的吸入性治疗实体的临床试验提供有效的进展。

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