Glucocorticoid Clearance and Metabolite Profiling in an In Vitro Human Airway Epithelium Lung Model

Abstract

The emergence of microphysiologic epithelial lung models using human cells in a physiologically relevant microenvironment has the potential to be a powerful tool for preclinical drug development and to improve predictive power regarding in vivo drug clearance. In this study, an in vitro model of the airway comprising human primary lung epithelial cells cultured in a microfluidic platform was used to establish a physiologic state and to observe metabolic changes as a function of glucocorticoid exposure. Evaluation of mucus production rate and barrier function, along with lung-specific markers, demonstrated that the lungs maintained a differentiated phenotype. Initial concentrations of 100 nM hydrocortisone (HC) and 30 nM cortisone (C) were used to evaluate drug clearance and metabolite production. Measurements made using ultra-high-performance liquid chromatography and high-mass-accuracy mass spectrometry indicated that HC metabolism resulted in the production of C and dihydrocortisone (diHC). When the airway model was exposed to C, diHC was identified; however, no conversion to HC was observed. Multicompartmental modeling was used to characterize the lung bioreactor data, and pharmacokinetic parameters, including elimination clearance and elimination half-life, were estimated. Polymerse chain reaction data confirmed overexpression of 11-b hydroxysteroid dehydrogenase 2 (11bHSD2) over 11bHSD1, which is biologically relevant to human lung. Faster metabolism was observed relative to a static model on elevated rates of C and diHC formation. Overall, our results demonstrate that this lung airway model has been successfully developed and could interact with other human tissues in vitro to better predict in vivo drug behavior.

An Inflamed Human Alveolar Model for Testing the Efficiency of Anti-inflammatory Drugs in vitro

“…Also, these models have been employed to investigate the safety and efficacy of aerosolized and dry powder formulations for pulmonary drug delivery ( Hittinger et al, 2016 ), including that of steroid drugs ( Bur and Lehr, 2008 ; Haghi et al, 2015 ). Finally, an in vitro human airway model differentiated from primary human bronchial cells has been proposed for pharmacokinetics studies ( Rivera-Burgos et al, 2016 ). LPS is a major component of the outer membrane of Gram-negative bacteria, such as Haemophilus influenzae , which are considered one of the main causes of infectious lung diseases ( King, 2012 ).…”

Skin-on-a-Chip: Transepithelial Electrical Resistance and Extracellular Acidification Measurements through an Automated Air-Liquid Interface

“…This procedure lacks reproducibility and standardization without the option of offering high-throughput capability. Although the next generation of electrode chambers (such as the Endohm chamber) allowed the measurement without removing samples, media as well as reagents had to be applied manually in case of long-term culture and drug studies [ 23 ]. Thus, extended studies are often not possible, because old media cannot be removed from the chamber, and there is no option for automated perfusion of fresh media.…”