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Multiple pathways for fluoroquinolone secretion by human intestinal epithelial (Caco-2) cells
Simon Lowes1, Nicholas L Simmons
1Department of Physiological Sciences, University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne NE2 4HH, UK.
British Journal of Pharmacology
|March 6, 2002
Summary
This study reveals that grepafloxacin, a fluoroquinolone antibiotic, is secreted from the intestine via MRP2 and MDR1 transporters. Ciprofloxacin, however, is not a substrate for these transporters, indicating differential transport mechanisms for fluoroquinolones.
Area of Science:
- Pharmacology
- Cell Biology
- Drug Transport
Background:
- Fluoroquinolones are widely used antibiotics, but their intestinal transport mechanisms remain incompletely understood.
- Understanding the efflux pathways is crucial for optimizing drug efficacy and minimizing toxicity.
Purpose of the Study:
- To elucidate the mechanistic basis of transintestinal fluoroquinolone secretion.
- To determine the roles of multidrug resistance protein 2 (MRP2) and multidrug resistance protein 1 (MDR1) in the intestinal transport of fluoroquinolones.
Main Methods:
- Utilized human intestinal epithelial cell lines (Caco-2, T84) and MDCKII cells transfected with human MDR1.
- Investigated the secretion of grepafloxacin and ciprofloxacin using radiolabeled compounds and transporter inhibitors.
- Assessed the involvement of MRP2 and MDR1 through gene expression and functional assays.
Main Results:
- Grepafloxacin secretion across Caco-2 cells was saturable and ATP-dependent, suggesting active transport.
- Grepafloxacin inhibited ciprofloxacin secretion and increased its cellular accumulation, indicating competition for apical export.
- Cholic acid secretion was MRP2-dependent and inhibited by grepafloxacin, but not ciprofloxacin.
- MDCKII-MDR1 cells showed increased grepafloxacin secretion, confirming MDR1 substrate activity, while ciprofloxacin and cholic acid were not substrates.
- T84 cells (MDR1+, MRP2-) showed limited grepafloxacin secretion, highlighting the role of MRP2.
Conclusions:
- Transepithelial secretion of grepafloxacin is mediated by both MRP2 and MDR1 transporters.
- Ciprofloxacin is not a substrate for MRP2 or MDR1 in the studied models.
- Grepafloxacin competes with ciprofloxacin for a shared transport pathway, the identity of which requires further investigation.