Drug transport across the human respiratory epithelial barrier
Citation:Johanna J. Salomon, 'Drug transport across the human respiratory epithelial barrier', [thesis], Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical Sciences, 2012, pp 333
Salomon TCD THESIS 9842 Drug transport.pdf (PDF) 176.7Mb
Drug transporters have only recently moved into the centre of attention of pulmonary drug delivery research, and of the more than 400 identified transporter proteins, only little information is available. In a first step, protein expression levels of several members of the ABC- and SLC-super family were determined in human lung epithelial cells and human alveolar epithelial primary cells. Protein abundance was found to be more or less equivalent for organic cation/camitine (OCT/N, SLC22A1-5) and multidrug and toxin extrusion (MATEl, SLC47A1) transporters in human alveolar (primary culture and A549), bronchiolar (H441), bronchial (16HBE14o-, Calu-3) epithelial cells, except for 0CT2 (not detected in bronchial cells), 0CTN2 (higher expression levels in the bronchial cells). The expression pattern of OATPs revealed high protein levels of 0ATP2A1, 0ATP3A1 and OATP4A1 in alveolar (primary cell culture and A549) cells, whereas low levels of transport proteins were detected in 16HBE140- and Calu-3 cells. Intestinal Caco-2 epithelial cells were used as comparison. P-glycoprotein (ABCB1IMDK-X) protein expression was confirmed in A549 and H441 cells. Our investigations continued by functionally characterising in particular OCT/Ns in human respiratory cell culture models by using a fluorescently- labelled cationic compound 4-(4 (dimethylamino)styryl)-N-methylpyridinium iodide (ASP+) as well as radiolabelled substrates, e.g., the model cation [14C]-TEA and the OCTN probe [3H]-acetylcarnitine in cell uptake studies. We showed that A549 cells exhibited the highest uptake activity of organic cations in comparison to the other cell types. In A549 cells we found evidence that the uptake of organic cations was mediated mainly by OCTl and 0CT2 at the alveolar epithelium. An OCT-driven uptake of organic cations has been shown at the bronchial and bronchiolar epithelium at lower levels with a speculative involvement of OCTl. In the case of acetylcarnitine uptake.
Author: Salomon, Johanna J.
Publisher:Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical Sciences
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Type of material:thesis
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