Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109, USA.
Pharm Res. 2010 Mar;27(3):457-67. doi: 10.1007/s11095-009-0034-9. Epub 2010 Jan 23.
For optimizing the local, pulmonary targeting of inhaled medications, it is important to analyze the relationship between the physicochemical properties of small molecules and their absorption, retention and distribution in the various cell types of the airways and alveoli.
A computational, multiscale, cell-based model was constructed to facilitate analysis of pulmonary drug transport and distribution. The relationship between the physicochemical properties and pharmacokinetic profile of monobasic molecules was explored. Experimental absorption data of compounds with diverse structures were used to validate this model. Simulations were performed to evaluate the effect of active transport and organelle sequestration on the absorption kinetics of compounds.
Relating the physicochemical properties to the pharmacokinetic profiles of small molecules reveals how the absorption half-life and distribution of compounds are expected to vary in different cell types and anatomical regions of the lung. Based on logP, pK(a) and molecular radius, the absorption rate constants (K(a)) calculated with the model were consistent with experimental measurements of pulmonary drug absorption.
The cell-based mechanistic model developed herein is an important step towards the rational design of local, lung-targeted medications, facilitating the design and interpretation of experiments aimed at optimizing drug transport properties in lung.
为了优化吸入药物的局部肺部靶向作用，分析小分子的物理化学性质与其在气道和肺泡的各种细胞类型中的吸收、保留和分布之间的关系非常重要。
构建了一个计算型、多尺度、基于细胞的模型，以方便分析肺部药物的转运和分布。探讨了一元小分子的物理化学性质和药代动力学特征之间的关系。使用具有不同结构的化合物的实验吸收数据对该模型进行了验证。模拟了主动转运和细胞器隔离对化合物吸收动力学的影响。
将物理化学性质与小分子的药代动力学特征相关联，揭示了化合物的吸收半衰期和分布在不同细胞类型和肺的解剖区域中的预期变化。基于 logP、pK(a) 和分子半径，模型计算得出的吸收速率常数 (K(a)) 与肺部药物吸收的实验测量结果一致。
本文开发的基于细胞的机制模型是朝着合理设计局部肺部靶向药物迈出的重要一步，有助于设计和解释旨在优化肺部药物转运特性的实验。
