In Vitro-In Silico Modeling of Caffeine and Diclofenac Permeation in Static and Fluidic Systems with a 16HBE Lung Cell Barrier.

Lukas Kovar,Dominik Selzer,Lena Wien,Robert Bals,Yvonne Kohl,Thorsten Lehr

doi:10.3390/ph15020250

Lukas Kovar, Dominik Selzer + Show 4 more

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https://doi.org/10.3390/ph15020250

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Abstract

Static in vitro permeation experiments are commonly used to gain insights into the permeation properties of drug substances but exhibit limitations due to missing physiologic cell stimuli. Thus, fluidic systems integrating stimuli, such as physicochemical fluxes, have been developed. However, as fluidic in vitro studies display higher complexity compared to static systems, analysis of experimental readouts is challenging. Here, the integration of in silico tools holds the potential to evaluate fluidic experiments and to investigate specific simulation scenarios. This study aimed to develop in silico models that describe and predict the permeation and disposition of two model substances in a static and fluidic in vitro system. For this, in vitro permeation studies with a 16HBE cellular barrier under both static and fluidic conditions were performed over 72 h. In silico models were implemented and employed to describe and predict concentration–time profiles of caffeine and diclofenac in various experimental setups. For both substances, in silico modeling identified reduced apparent permeabilities in the fluidic compared to the static cellular setting. The developed in vitro–in silico modeling framework can be expanded further, integrating additional cell tissues in the fluidic system, and can be employed in future studies to model pharmacokinetic and pharmacodynamic drug behavior.

Highlights

Compared to the cell viability in the static system, which was defined as 100% with a standard deviation of 15.2% (n = 3), the viability under
The estimated apparent permeabilities from static in vitro experiments could be used to predict the behavior of the compounds in the fluidic system under control conditions
A decreased permeability in the fluidic setting compared to the static experimental design had to be estimated for a precise description of the observed caffeine and diclofenac concentrations in the fluidic cell experiments with 16HBE cells

Summary

Introduction

Further investigations into how in vitro and in silico approaches can support overcoming the limitations of current preclinical methods whilst reducing the need for animal studies are required [3]. In vitro permeation experiments can be used to characterize the transport of drug molecules across biological barriers, such as the pulmonary [4,5,6] or intestinal epithelia [7,8,9] barrier. The information gained in permeation studies on the properties of drug substances or environmental pollutants and their interaction with permeation barriers can be employed to estimate transport through physiologic endothelial and epithelial barriers in vivo [7,10,11,12]. A common approach for investigating the respective apparent permeability through a cell monolayer in vitro is the application of a single-barrier model [9,11,13]

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