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The Extracellular Microenvironment Explains Variations in Passive Drug Transport Across Different Airway Epithelial Cell Types

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ABSTRACT

Purpose

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.

Conclusion

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.

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Abbreviations

4-OHP:

4-hydroxypropranolol

DMEM:

Dulbecco’s Modified Eagle Medium

FBS:

Fetal bovine serum

LC/MS:

Liquid chromatography-mass spectrometry

LY:

Lucifer yellow

N-DIP:

N-desisopropyl propranolol

PR:

Propranolol

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by NIH grant R01GM078200 (G. R. Rosania). K. A. Min was supported by the Warner Lambert/Parke Davis Fellowship, University of Michigan College of Pharmacy and the Rackham Pre-doctoral Fellowship. The authors would like to acknowledge and thank the staff of the University of Michigan Microscopy and Image Analysis Laboratory for their technical assistance.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Kyoung Ah Min, Arjang Talattof, Yasuhiro Tsume, Jing-yu Yu & Gus R. Rosania

  2. Department of Clinical, Social, & Administrative Sciences College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Kathleen A. Stringer

  3. Department of Bioengineering, University of California at San Diego Jacobs School of Engineering, La Jolla, California, 92093, USA

    Dong Hyun Lim

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  1. Kyoung Ah Min
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Correspondence to Gus R. Rosania.

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Min, K.A., Talattof, A., Tsume, Y. et al. The Extracellular Microenvironment Explains Variations in Passive Drug Transport Across Different Airway Epithelial Cell Types. Pharm Res 30, 2118–2132 (2013). https://doi.org/10.1007/s11095-013-1069-5

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  • DOI: https://doi.org/10.1007/s11095-013-1069-5

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