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

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

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
287 Downloads (Pure)

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 was 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.
Original languageEnglish
Pages (from-to)74-82
Number of pages9
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume86
Issue number1
Early online date28 Jun 2013
DOIs
Publication statusPublished - Jan 2014

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