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Glucocorticoid Clearance and Metabolite Profiling in an In Vitro Human Airway Epithelium Lung Model.
Rivera-Burgos, Dinelia; Sarkar, Ujjal; Lever, Amanda R; Avram, Michael J; Coppeta, Jonathan R; Wishnok, John S; Borenstein, Jeffrey T; Tannenbaum, Steven R.
Afiliación
  • Rivera-Burgos D; Department of Biological Engineering (D.R.B., U.S., J.S.W., S.R.T.), and Department of Chemistry (S.R.T.), Massachusetts Institute of Technology, and The Charles Stark Draper Laboratory (A.R.L., J.R.C., J.T.B.), Cambridge, Massachusetts; and Northwestern University, Feinberg School of Medicine, Chic
  • Sarkar U; Department of Biological Engineering (D.R.B., U.S., J.S.W., S.R.T.), and Department of Chemistry (S.R.T.), Massachusetts Institute of Technology, and The Charles Stark Draper Laboratory (A.R.L., J.R.C., J.T.B.), Cambridge, Massachusetts; and Northwestern University, Feinberg School of Medicine, Chic
  • Lever AR; Department of Biological Engineering (D.R.B., U.S., J.S.W., S.R.T.), and Department of Chemistry (S.R.T.), Massachusetts Institute of Technology, and The Charles Stark Draper Laboratory (A.R.L., J.R.C., J.T.B.), Cambridge, Massachusetts; and Northwestern University, Feinberg School of Medicine, Chic
  • Avram MJ; Department of Biological Engineering (D.R.B., U.S., J.S.W., S.R.T.), and Department of Chemistry (S.R.T.), Massachusetts Institute of Technology, and The Charles Stark Draper Laboratory (A.R.L., J.R.C., J.T.B.), Cambridge, Massachusetts; and Northwestern University, Feinberg School of Medicine, Chic
  • Coppeta JR; Department of Biological Engineering (D.R.B., U.S., J.S.W., S.R.T.), and Department of Chemistry (S.R.T.), Massachusetts Institute of Technology, and The Charles Stark Draper Laboratory (A.R.L., J.R.C., J.T.B.), Cambridge, Massachusetts; and Northwestern University, Feinberg School of Medicine, Chic
  • Wishnok JS; Department of Biological Engineering (D.R.B., U.S., J.S.W., S.R.T.), and Department of Chemistry (S.R.T.), Massachusetts Institute of Technology, and The Charles Stark Draper Laboratory (A.R.L., J.R.C., J.T.B.), Cambridge, Massachusetts; and Northwestern University, Feinberg School of Medicine, Chic
  • Borenstein JT; Department of Biological Engineering (D.R.B., U.S., J.S.W., S.R.T.), and Department of Chemistry (S.R.T.), Massachusetts Institute of Technology, and The Charles Stark Draper Laboratory (A.R.L., J.R.C., J.T.B.), Cambridge, Massachusetts; and Northwestern University, Feinberg School of Medicine, Chic
  • Tannenbaum SR; Department of Biological Engineering (D.R.B., U.S., J.S.W., S.R.T.), and Department of Chemistry (S.R.T.), Massachusetts Institute of Technology, and The Charles Stark Draper Laboratory (A.R.L., J.R.C., J.T.B.), Cambridge, Massachusetts; and Northwestern University, Feinberg School of Medicine, Chic
Drug Metab Dispos ; 44(2): 220-6, 2016 Feb.
Article en En | MEDLINE | ID: mdl-26586376
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-ß hydroxysteroid dehydrogenase 2 (11ßHSD2) over 11ßHSD1, 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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Mucosa Respiratoria / Células Epiteliales / Glucocorticoides / Pulmón Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Drug Metab Dispos Asunto de la revista: FARMACOLOGIA Año: 2016 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Mucosa Respiratoria / Células Epiteliales / Glucocorticoides / Pulmón Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Drug Metab Dispos Asunto de la revista: FARMACOLOGIA Año: 2016 Tipo del documento: Article