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Research ArticleArticle

Transporter Studies with the 3-O-Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Kidney Drug Transporters

Yong-Hae Han, Dennis Busler, Yang Hong, Yuan Tian, Cliff Chen and A. David Rodrigues
Drug Metabolism and Disposition July 2010, 38 (7) 1064-1071; DOI: https://doi.org/10.1124/dmd.109.031526
Yong-Hae Han
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Dennis Busler
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Yang Hong
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Yuan Tian
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Cliff Chen
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A. David Rodrigues
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Abstract

17α-Ethinylestradiol (EE2), a synthetic and potent estrogen receptor agonist, is extensively metabolized in both intestine and liver and is largely excreted in bile and urine as the 3-O-sulfate (EE2-Sul) and 3-O-glucuronide. In the present study, EE2-Sul was evaluated as a substrate of various transporters known to be expressed in the kidney. Uptake studies were performed with human epithelial cells [human embryonic kidney (HEK)-293] that contained individually expressed organic cation transporter 2 (OCT2), organic anion transporter (OAT) forms 3 and 4, and multidrug and toxin extrusion 1 (MATE1). The transporter phenotyping studies were extended to include insect cell (Sf9) membrane vesicles that expressed multidrug resistance-associated protein 4 (MRP4) and Madin-Darby canine kidney cells that expressed OAT1. Based on the results obtained, we concluded that EE2-Sul serves as a substrate of OAT3 and OAT4, but not OCT2, OAT1, MATE1, and MRP4. First, EE2-Sul uptake was highly increased in OAT3/HEK-293 cells (versus mock/HEK-293 cells) and was inhibited by OAT3 inhibitors such as bromosulfophthalein (BSP), cimetidine, and probenecid. OAT3-mediated uptake also conformed to single-Km (Michaelis constant) kinetics (Km = 21.1 μM). Second, EE2-Sul uptake was also significantly higher in OAT4/HEK-293 cells and was inhibited by BSP, methotrexate, and probenecid. In contrast to OAT3, OAT4-dependent uptake was characterized by a two-Km model (Km1 = 1.6 μM; Km2 = 195 μM). Based on the results of this study, we hypothesize that EE2-Sul is taken up into renal proximal tubule cells by OAT3, and OAT4 plays a role in its secretion into the renal brush border lumen.

Footnotes

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

    doi:10.1124/dmd.109.031526.

  • ABBREVIATIONS:

    EE2
    17α-ethinylestradiol
    EE2-Sul
    17α-ethinylestradiol-3-O-sulfate
    EE2-Glu
    17α-ethinylestradiol-3-O-glucuronide
    OAT
    organic anion transporter
    NTCP
    sodium-taurocholate cotransporting polypeptide
    BCRP
    breast cancer resistance protein
    SLC
    solute carrier
    ABC
    ATP-binding cassette
    OATP
    organic anion-transporting polypeptide
    OCT
    organic cation transporter
    MRP
    multidrug resistance-associated protein
    MATE1
    multidrug and toxin extrusion
    MDCK
    Madin-Darby canine kidney
    HEK
    human embryonic kidney
    PAH
    para-aminohippurate
    MPP
    1-methyl-4-phenylpyridinium
    FRT
    Flp recombination target
    PAPS
    3′-phosphoadenosine 5′-phosphosulfate
    HPLC
    high-performance liquid chromatography
    PCR
    polymerase chain reaction
    RQ
    relative quantification
    HBSS
    Hank's balanced salt solution
    BSP
    bromosulfophthalein
    DHEAS
    dehydroepiandrosterone-3-sulfate
    SN-38
    7-ethyl-10-hydroxy-camptothecin.

  • Received December 2, 2009.
  • Accepted April 1, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Research ArticleArticle

Transporter Studies with the 3-O-Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Kidney Drug Transporters

Yong-Hae Han, Dennis Busler, Yang Hong, Yuan Tian, Cliff Chen and A. David Rodrigues
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1064-1071; DOI: https://doi.org/10.1124/dmd.109.031526

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Research ArticleArticle

Transporter Studies with the 3-O-Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Kidney Drug Transporters

Yong-Hae Han, Dennis Busler, Yang Hong, Yuan Tian, Cliff Chen and A. David Rodrigues
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1064-1071; DOI: https://doi.org/10.1124/dmd.109.031526
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