Cell-based multiscale computational modeling of small molecule absorption and retention in the lungs.

Pharmaceutical Research
Jing-Yu Yu, Gus R Rosania

Abstract

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 imp...Continue Reading

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Citations

Dec 16, 2010·The Journal of Pharmacology and Experimental Therapeutics·Nan ZhengGus R Rosania
Mar 3, 2012·PLoS Computational Biology·Jing-Yu YuGus R Rosania
Mar 15, 2014·PLoS Computational Biology·Lars Ole SchwenLars Kuepfer
Jul 26, 2016·Frontiers in Pharmacology·Eleonore FröhlichSharareh Salar-Behzadi
Dec 23, 2017·International Journal for Numerical Methods in Biomedical Engineering·Ravishekar Ravi KannanAndrzej Przekwas
May 29, 2019·Molecular Pharmaceutics·Johanna ErikssonHans Lennernäs

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