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Digoxin net secretory transport in bronchial epithelial cell layers is not exclusively mediated by P-glycoprotein/MDR1

Hutter, Victoria; Chau, David Y.S.; Hilgendorf, Constanze; Brown, Alan; Cooper, Anne; Zann, Vanessa; Pritchard, David I.; Bosquillon, Cynthia

Authors

Victoria Hutter

David Y.S. Chau

Constanze Hilgendorf

Alan Brown

Anne Cooper

Vanessa Zann

David I. Pritchard



Abstract

The impact of P-glycoprotein (MDR1, ABCB1) on drug disposition in the lungs as well as its presence and activity in in vitro respiratory drug absorption models remain controversial to date. Hence, we characterised MDR1 expression and the bidirectional transport of the common MDR1 probe 3H-digoxin in air-liquid interfaced (ALI) layers of normal human bronchial epithelial (NHBE) cells and of the Calu-3 bronchial epithelial cell line at different passage numbers. Madin-Darby Canine Kidney (MDCKII) cells transfected with the human MDR1 were used as positive controls. 3H-digoxin efflux ratio (ER) was low and highly variable in NHBE layers. In contrast, ER = 11.4 or 3.0 were measured in Calu-3 layers at a low or high passage number, respectively. These were, however, in contradiction with increased MDR1 protein levels observed upon passaging. Furthermore, ATP depletion and the two MDR1 inhibitory antibodies MRK16 and UIC2 had no or only a marginal impact on 3H-digoxin net secretory transport in the cell line. Our data do not support an exclusive role of MDR1 in 3H-digoxin apparent efflux in ALI Calu-3 layers and suggest the participation of an ATP-independent carrier. Identification of this transporter might provide a better understanding of drug distribution in the lungs.© 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Hutter, V., Chau, D. Y., Hilgendorf, C., Brown, A., Cooper, A., Zann, V., …Bosquillon, C. (2014). Digoxin net secretory transport in bronchial epithelial cell layers is not exclusively mediated by P-glycoprotein/MDR1. European Journal of Pharmaceutics and Biopharmaceutics, 86(1), 74-82. https://doi.org/10.1016/j.ejpb.2013.06.010

Journal Article Type Article
Acceptance Date Jun 10, 2013
Online Publication Date Jun 28, 2013
Publication Date 2014-01
Deposit Date Nov 16, 2017
Journal European Journal of Pharmaceutics and Biopharmaceutics
Print ISSN 0939-6411
Electronic ISSN 1873-3441
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 86
Issue 1
Pages 74-82
DOI https://doi.org/10.1016/j.ejpb.2013.06.010
Public URL http://dx.doi.org/10.1016/j.ejpb.2013.06.010
Publisher URL https://www.sciencedirect.com/science/article/pii/S0939641113002294