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Cell-Based Multiscale Computational Modeling of Small Molecule Absorption and Retention in the Lungs

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Abstract

Purpose

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.

Methods

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.

Results

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, pKa and molecular radius, the absorption rate constants (Ka) calculated with the model were consistent with experimental measurements of pulmonary drug absorption.

Conclusions

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.

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ACKNOWLEDGEMENTS

This work was supported by NIH Grant RO1GM078200 to G. Rosania, and by a Fred Lyons Jr. Fellowship from the College of Pharmacy at University of Michigan to J. Yu. The authors thank Newaj Abdullah for collecting lung-relevant parameters.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Jing-yu Yu

  2. Department of Pharmaceutical Science, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109, USA

    Gus R. Rosania

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  1. Jing-yu Yu
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  2. Gus R. Rosania
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Correspondence to Gus R. Rosania.

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Yu, Jy., Rosania, G.R. Cell-Based Multiscale Computational Modeling of Small Molecule Absorption and Retention in the Lungs. Pharm Res 27, 457–467 (2010). https://doi.org/10.1007/s11095-009-0034-9

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  • DOI: https://doi.org/10.1007/s11095-009-0034-9

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