Journal article
Kinetic identification of membrane transporters that assist P-glycoprotein-mediated transport of digoxin and loperamide through a confluent monolayer of MDCKII-hMDR1 cells
Drug metabolism and disposition, v 36(2), pp 452-460
01 Feb 2008
PMID: 17967933
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
A robust screen for compound interaction with P-glycoprotein (P-gp) has some obvious requirements, such as a cell line expressing P-gp and a probe substrate that is transported solely by P-gp and passive permeability. It is actually difficult to prove that a particular probe substrate interacts only with P-gp in the chosen cell line. Using a confluent monolayer of MDCKII-hMDR1 cells, we have determined the elementary rate constants for the P-gp efflux of amprenavir, digoxin, loperamide, and quinidine. For amprenavir and quinidine, transport was fitted with just P- gp and passive permeability. For digoxin and loperamide, fitting required a basolateral transporter (p < 0.01), which was inhibited by the P- gp inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). This means that when digoxin is used as a probe substrate and a compound is shown to inhibit digoxin flux, it could be that the inhibition occurs at the basolateral transporter rather than at P-gp. Digoxin basolateral > apical efflux also required an apical importer (p < 0.05). We propose that amprenavir and quinidine are robust probe substrates for assessing P-gp interactions using the MDCKII-hMDR1 confluent cell monolayer. Usage of another cell line, e. g., LLC-hMDR1 or Caco-2, would require the same kinetic validation to ensure that the probe substrate interacts only with P-gp. Attempts to identify the additional digoxin and loperamide transporters using a wide range of substrates/inhibitors of known epithelial transporters (organic cation transporters, organic anion transporters, organic ion- transporting polypeptide, uric acid transporter, or multidrug resistance- associated protein) failed to inhibit the digoxin or loperamide transport through their basolateral transporter.
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Details
- Title
- Kinetic identification of membrane transporters that assist P-glycoprotein-mediated transport of digoxin and loperamide through a confluent monolayer of MDCKII-hMDR1 cells
- Creators
- Poulomi Acharya - Drexel UniversityMichael P. O'Connor - Drexel UniversityJoseph W. Polli - GlaxoSmithKline, Preclin Drug Metab & Pharmacokinet, Res Triangle Pk, NC USAAndrew Ayrton - Drexel UniversityHarma Ellens - GlaxoSmithKline, Preclin Drug Metab & Pharmacokinet, King Of Prussia, PA USAJoe Bentz - Drexel Univ, Dept Biosci & Biotechnol, Philadelphia, PA 19104 USA
- Publication Details
- Drug metabolism and disposition, v 36(2), pp 452-460
- Publisher
- Amer Soc Pharmacology Experimental Therapeutics
- Number of pages
- 9
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biodiversity, Earth, and Environmental Science (BEES); Biology
- Web of Science ID
- WOS:000252634900030
- Scopus ID
- 2-s2.0-38749113348
- Other Identifier
- 991019169356504721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy