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Research ArticleArticle

Intestinal Ciprofloxacin Efflux: The Role of Breast Cancer Resistance Protein (ABCG2)

I. S. Haslam, J. A. Wright, D. A. O'Reilly, D. J. Sherlock, T. Coleman and N. L. Simmons
Drug Metabolism and Disposition December 2011, 39 (12) 2321-2328; DOI: https://doi.org/10.1124/dmd.111.038323
I. S. Haslam
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J. A. Wright
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D. A. O'Reilly
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D. J. Sherlock
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T. Coleman
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N. L. Simmons
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Abstract

Intestinal secretory movement of the fluoroquinolone antibiotic, ciprofloxacin, may limit its oral bioavailability. Active ATP-binding cassette (ABC) transporters such as breast cancer resistance protein (BCRP) have been implicated in ciprofloxacin transport. The aim of this study was to test the hypothesis that BCRP alone mediates intestinal ciprofloxacin secretion. The involvement of ABC transport proteins in ciprofloxacin secretory flux was investigated with the combined use of transfected cell lines [bcrp1/BCRP-Madin-Darby canine kidney II (MDCKII) and multidrug resistance-related protein 4 (MRP4)-human embryonic kidney (HEK) 293] and human intestinal Caco-2 cells, combined with pharmacological inhibition using 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6, 7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143), cyclosporine, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), and verapamil as ABC-selective inhibitors. In addition, the regional variation in secretory capacity was investigated using male Han Wistar rat intestine mounted in Ussing chambers, and the first indicative measurements of ciprofloxacin transport by ex vivo human jejunum were made. Active, Ko143-sensitive ciprofloxacin secretion was observed in bcrp1-MDCKII cell layers, but in low-passage (BCRP-expressing) Caco-2 cell layers only a 54% fraction was Ko143-sensitive. Ciprofloxacin accumulation was lower in MRP4-HEK293 cells than in the parent line, indicating that ciprofloxacin is also a substrate for this transporter. Ciprofloxacin secretion by Caco-2 cell layers was not inhibited by MK571. Secretory flux showed marked regional variability in the rat intestine, increasing from the duodenum to peak in the ileum. Ciprofloxacin secretion was present in human jejunum and was reduced by Ko143 but showed marked interindividual variability. Ciprofloxacin is a substrate for human and rodent BCRP. An additional pathway for ciprofloxacin secretion exists in Caco-2 cells, which is unlikely to be MRP(4)-mediated. BCRP is likely to be the dominant transport mechanism for ciprofloxacin efflux in both rat and human jejunum.

Footnotes

  • J.A.W. was supported by a Biotechnology and Biological Sciences Research Council - Collaborative Awards in Science and Engineering award in conjunction with AstraZeneca.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.038323.

  • ABBREVIATIONS:

    ABC
    ATP-binding cassette
    P-gp
    P-glycoprotein
    MDR/mdr
    multidrug resistance protein
    MDCKII
    Madin-Darby canine kidney II
    BCRP/bcrp
    breast cancer resistance protein
    Ko143
    3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester
    MRP/mrp
    multidrug resistance-related protein
    h
    human
    KBR
    Krebs-Ringer bicarbonate
    PD
    potential difference
    HPLC
    high-performance liquid chromatography
    a
    apical
    b
    basal
    PA
    passage
    HEK
    human embryonic kidney
    PCR
    polymerase chain reaction
    q
    quantitative
    WT
    wild-type
    CsA
    cyclosporine
    DIDS
    4,4′-diisothiocyanostilbene-2,2′-disulfonic acid
    MK-571
    3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase.

  • Received January 28, 2011.
  • Accepted August 24, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (12)
Drug Metabolism and Disposition
Vol. 39, Issue 12
1 Dec 2011
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Research ArticleArticle

CIPROFLOXACIN ACTIVE TRANSPORT AND INTESTINAL SECRETION

I. S. Haslam, J. A. Wright, D. A. O'Reilly, D. J. Sherlock, T. Coleman and N. L. Simmons
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2321-2328; DOI: https://doi.org/10.1124/dmd.111.038323

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Research ArticleArticle

CIPROFLOXACIN ACTIVE TRANSPORT AND INTESTINAL SECRETION

I. S. Haslam, J. A. Wright, D. A. O'Reilly, D. J. Sherlock, T. Coleman and N. L. Simmons
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2321-2328; DOI: https://doi.org/10.1124/dmd.111.038323
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