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Rifampin and digoxin induction of MDR1 expression and function in human intestinal (T84) epithelial cells
I S Haslam1, K Jones, T Coleman
1Epithelial Research Group, Institute for Cell and Molecular Biosciences, University of Newcastle Upon Tyne, Medical School, Newcastle Upon Tyne, UK.
British Journal of Pharmacology
|March 12, 2008
Summary
Digoxin significantly increases intestinal P-glycoprotein (MDR1) expression and transport in T84 cells, distinct from rifampin
Area of Science:
- Pharmacology
- Cell Biology
- Drug Transport
Background:
- Intestinal P-glycoprotein (MDR1) limits oral drug bioavailability.
- MDR1 expression is regulated by nuclear receptors like pregnane X receptor (PXR).
- T84 cells co-express MDR1 and PXR, serving as a model for intestinal drug transport.
Purpose of the Study:
- To investigate the dynamic regulation of MDR1 transport capacity in T84 cells.
- To assess the effects of rifampin (PXR agonist) and digoxin (MDR1 substrate) on MDR1 expression and function.
Main Methods:
- T84 cells were pre-exposed to rifampin or digoxin.
- Transepithelial digoxin fluxes were measured to assess MDR1 transport activity.
- Quantitative PCR, Western blotting, and immunocytochemistry quantified MDR1 and PXR levels.
Main Results:
- Rifampin increased MDR1 transcript, protein, and functional activity.
- Digoxin significantly upregulated MDR1 transcript, total protein, apical protein, and functional activity.
- Rifampin increased PXR expression, while digoxin decreased it.
Conclusions:
- Chronic digoxin exposure markedly upregulates MDR1 expression and secretory capacity in T84 epithelia.
- Digoxin-induced MDR1 changes are distinct from PXR-mediated effects of rifampin.
- T84 cells are a valuable model for studying drug transporter regulation.
