Glucocorticoid clearance and metabolite profiling in an in vitro human airway epithelium lung model

Dinelia Rivera-Burgos, Ujjal Sarkar, Amanda R. Lever, Michael J. Avram, Jonathan R. Coppeta, John S. Wishnok, Jeffrey T. Borenstein, Steven R. Tannenbaum*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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, anin vitro model of the airway comprisinghuman 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-β hydroxysteroid dehydrogenase 2 (11βHSD2) over 11βHSD1, 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.

Original languageEnglish (US)
Pages (from-to)220-226
Number of pages7
JournalDrug Metabolism and Disposition
Volume44
Issue number2
DOIs
StatePublished - Feb 1 2016

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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