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

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        906784.pdf (PDF, 885Kb)
        Author
        Hutter, Victoria
        Chau, David Y.S.
        Hilgendorf, Constanze
        Brown, Alan
        Cooper, Anne
        Zann, Vanessa
        Pritchard, David I.
        Bosquillon, Cynthia
        Attention
        2299/13420
        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.
        Publication date
        2014-01
        Published in
        European Journal of Pharmaceutics and Biopharmaceutics
        Published version
        https://doi.org/10.1016/j.ejpb.2013.06.010
        Other links
        http://hdl.handle.net/2299/13420
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