Document Detail

Multiple pathways for fluoroquinolone secretion by human intestinal epithelial (Caco-2) cells.
MedLine Citation:
PMID:  11877335     Owner:  NLM     Status:  MEDLINE    
1. Human intestinal epithelial Caco-2 cells, T84 cells, and MDCKII cells transfected with human MDR1, were used to investigate the mechanistic basis of transintestinal fluoroquinolone secretion. 2. The fluoroquinolone grepafloxacin was secreted across Caco-2 monolayers by a saturable process (V(max)=16.9 +/- 3.4 Net secretion was reduced by 2-deoxyglucose/azide treatment to reduce intracellular ATP. 3. Grepafloxacin inhibited [(14)C]-ciprofloxacin (100 microM) secretion across Caco-2 monolayers (K(0.5)=0.8 mM), and concurrently increased the cellular accumulation of ciprofloxacin from the basal medium, indicating inhibition of export across the apical membrane. 4. The unconjugated bile acid, cholic acid, was secreted across Caco-2 monolayers, and this secretion was sensitive to inhibition by the MRP-selective inhibitor MK-571, suggesting MRP2 involvement. Secretion of cholic acid (10 microM) across the apical membrane was also inhibited by grepafloxacin (K(0.5)=0.3 mM), but not by ciprofloxacin. 5. In MDCKII-MDR1 monolayers, net secretion of grepafloxacin was increased by 3.5 fold compared with untransfected controls. Neither ciprofloxacin nor cholic acid showed net secretion in either MDCKII or MDCKII-MDR1 monolayers, showing that in contrast to grepafloxacin, neither are substrates for MDR1. 6. In T84 monolayers, which express MDR1 but not MRP2, neither ciprofloxacin nor cholic acid was secreted, whilst the V(max) for grepafloxacin secretion was lower than in Caco-2 cells, which express both MDR1 and MRP2. 7. In conclusion, the transepithelial secretion of grepafloxacin is mediated by both MRP2 and MDR1, whereas ciprofloxacin is a substrate for neither. Grepafloxacin also competes for the ciprofloxacin-sensitive pathway, which remains to be elucidated.
Simon Lowes; Nicholas L Simmons
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  British journal of pharmacology     Volume:  135     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-03-05     Completed Date:  2002-08-16     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1263-75     Citation Subset:  IM    
Department of Physiological Sciences, University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne NE2 4HH, UK.
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MeSH Terms
Anti-Infective Agents / pharmacokinetics
Biological Transport
Caco-2 Cells
Ciprofloxacin / pharmacokinetics
Fluoroquinolones / pharmacokinetics*
Intestinal Mucosa / metabolism*
Membrane Transport Proteins*
Multidrug Resistance-Associated Proteins / metabolism*
P-Glycoprotein / metabolism*
Piperazines / pharmacokinetics
Reg. No./Substance:
0/Anti-Infective Agents; 0/Fluoroquinolones; 0/Membrane Transport Proteins; 0/Multidrug Resistance-Associated Proteins; 0/P-Glycoprotein; 0/Piperazines; 0/multidrug resistance-associated protein 1; 0/multidrug resistance-associated protein 2; 85721-33-1/Ciprofloxacin; L1M1U2HC31/grepafloxacin

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