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Research ArticleArticle

Utility of P-Glycoprotein and Organic Cation Transporter 1 Double-Transfected LLC-PK1 Cells for Studying the Interaction of YM155 Monobromide, Novel Small-Molecule Survivin Suppressant, with P-Glycoprotein

Megumi Iwai, Tsuyoshi Minematsu, Qun Li, Takafumi Iwatsubo and Takashi Usui
Drug Metabolism and Disposition December 2011, 39 (12) 2314-2320; DOI: https://doi.org/10.1124/dmd.111.040733
Megumi Iwai
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Tsuyoshi Minematsu
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Qun Li
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Takafumi Iwatsubo
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Takashi Usui
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Abstract

1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide), a novel small molecule that downregulates survivin and exhibits potent antitumor activity, is hydrophilic and cationic. Although previous studies have shown that influx transporters play important roles in the uptake of YM155 into hepatocytes and possibly into cancer cells, efflux transporters have yet to be investigated. In this study, we assessed the interaction of YM155 with P-glycoprotein [multidrug resistance 1 (MDR1)/ATP-binding cassette B1] using two kinds of transcellular transport systems: Caco-2 and MDR1-expressing LLC-PK1 cells (LLC-MDR1). We also used a newly established LLC-OCT1/MDR1 cell line, which expresses basal YM155 uptake transporter organic cation transporter1 (OCT1) and apical MDR1. Direct interaction between YM155 and MDR1 and other efflux transporters was evaluated using transporter-expressing membrane vesicles. A bidirectional transporter assay using Caco-2 and LLC-MDR1 cells showed low permeability and no vectorial transport of YM155, suggesting that YM155 is not a substrate of MDR1. However, vectorial transport across LLC-OCT1/MDR1 cells was identified, which was inhibited by the MDR1 inhibitor cyclosporine A, clearly indicating that YM155 is in fact a substrate of MDR1. Insufficient expression of basal uptake transporter of YM155 in Caco-2 and LLC-MDR1 might have confounded conclusions regarding YM155 and MDR1. Using the transporter-expressing vesicles, MDR1-mediated transport was most significantly involved in YM155 transport among the efflux transporters examined. In conclusion, these findings suggest that YM155 is a substrate of MDR1, and that MDR1 may play an important role in the pharmacokinetics of YM155. Transcellular assays lacking basal uptake transporters may be inaccurate in the assessment of hydrophilic compounds that have poor membrane permeability by passive diffusion.

Footnotes

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

    doi:10.1124/dmd.111.040733.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    YM155 monobromide
    1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide
    OCT
    organic cation transporter
    ABC
    ATP-binding cassette
    MDCKII
    Madin-Darby canine kidney II
    MPP
    1-methyl-4-phenylpyridinium
    MRP
    multidrug resistance-associated protein
    P-gp/MDR1
    P-glycoprotein/multidrug resistance 1
    BCRP
    breast cancer resistance protein
    CysA
    cyclosporine A.

  • Received July 21, 2011.
  • Accepted September 14, 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

INTERACTION OF YM155 WITH P-GLYCOPROTEIN

Megumi Iwai, Tsuyoshi Minematsu, Qun Li, Takafumi Iwatsubo and Takashi Usui
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2314-2320; DOI: https://doi.org/10.1124/dmd.111.040733

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Research ArticleArticle

INTERACTION OF YM155 WITH P-GLYCOPROTEIN

Megumi Iwai, Tsuyoshi Minematsu, Qun Li, Takafumi Iwatsubo and Takashi Usui
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2314-2320; DOI: https://doi.org/10.1124/dmd.111.040733
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