title: The extracellular microenvironment explains variations in passive drug transport across different airway epithelial cell types.
abstract: OBJECTIVE
  We sought to identify key variables in cellular architecture and physiology that might explain observed differences in the passive transport properties of small molecule drugs across different airway epithelial cell types.
  
  
  METHODS
  Propranolol (PR) was selected as a weakly basic, model compound to compare the transport properties of primary (NHBE) vs. tumor-derived (Calu-3) cells. Differentiated on Transwell™ inserts, the architecture of pure vs. mixed cell co-cultures was studied with confocal microscopy followed by quantitative morphometric analysis. Cellular pharmacokinetic modeling was used to identify parameters that differentially affect PR uptake and transport across these two cell types.
  
  
  RESULTS
  Pure Calu-3 and NHBE cells possessed different structural and functional properties. Nevertheless, mixed Calu-3 and NHBE cell co-cultures differentiated as stable cell monolayers. After measuring the total mass of PR, the fractional areas covered by Calu-3 and NHBE cells allowed deconvoluting the transport properties of each cell type. Based on the apparent thickness of the unstirred, cell surface aqueous layer, local differences in the extracellular microenvironment explained the measured variations in passive PR uptake and permeation between Calu-3 and NHBE cells.
  
  
  CONCLUSIONS
  Mixed cell co-cultures can be used to compare the local effects of the extracellular microenvironment on drug uptake and transport across two epithelial cell types.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Kyoung Ah
authors.initials: KA
authors.lastname: Min
authors.forename: Arjang
authors.initials: A
authors.lastname: Talattof
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsume
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Stringer
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Yu
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Lim
authors.forename: Gus R
authors.initials: GR
authors.lastname: Rosania
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D010539:Permeability; D010599:Pharmacokinetics; D011433:Propranolol / Q000493:pharmacokinetics*; D020545:Respiratory Mucosa / Q000378:metabolism*; D014867:Water / Q000378:metabolism
chemical_list: D014867:Water; D011433:Propranolol