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Research ArticleArticle

Transporter Studies with the 3-O-Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Liver 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) 1072-1082; DOI: https://doi.org/10.1124/dmd.109.031518
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 component of oral contraceptives, is known to undergo considerable first-pass 3-O-sulfation in the intestine and liver. Once formed, the 3-O-sulfate conjugate (EE2-Sul) is detected in circulation at appreciable levels (versus parent EE2) and is present in bile. Therefore, hepatic uptake of EE2-Sul was assessed with suspensions of cryopreserved human primary hepatocytes. In this instance, there was evidence for active (temperature-dependent) uptake, which was described by a two-Km (Michaelis constant) model (Km1 = 220 nM; Km2 = 15.5 μM). Uptake was inhibited (∼90%) by bromosulfophthalein but not by tetraethylammonium or p-aminohippurate. In agreement, EE2-Sul was shown to be a substrate of recombinant organic anion transporter peptides (OATP1B1 and OATP2B1), and Na+/taurocholate-cotransporting polypeptide (NTCP), expressed individually in human embryonic kidney (HEK) 293 cells. Transport by OATP1B1 was described by two Km values (87 nM and 141 μM), whereas OATP2B1- and NTCP-mediated uptake into HEK-293 cells conformed to single Km kinetics (10.7 and 2.6 μM, respectively). EE2-Sul was also assessed as an efflux transporter substrate using membrane vesicles expressing bile salt export pump, breast cancer resistance protein (BCRP), and individual forms of multidrug resistance-associated protein (MRP1, MRP2, and MRP3). Transport studies were also conducted with a cell line expression P-glycoprotein. Only vesicles that contained BCRP exhibited ATP-dependent uptake of EE2-Sul (Km1 = 2.9 and Km2 = 307 μM). Collectively, the data show that hepatic uptake of EE2-Sul can be mediated by three transporters (OATP1B1, OATP2B1, and NTCP), whereas biliary excretion of EE2-Sul into bile likely involves BCRP.

Footnotes

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

    doi:10.1124/dmd.109.031518.

  • ABBREVIATIONS:

    EE2
    17α-ethinylestradiol
    UGT
    UDP-glucuronosyltransferase
    EE2-Sul
    17α-ethinylestradiol-3-O-sulfate
    SULT
    sulfotransferase
    OAT
    organic anion transporter
    OCT
    organic cation transporter
    OATP
    organic anion-transporting polypeptide
    MRP
    multidrug resistance-associated protein
    BCRP
    breast cancer resistance protein
    P-gp
    P-glycoprotein
    BSEP
    bile salt export pump
    EE2-Glu
    17α-ethinylestradiol 3-O-glucuronide
    HEK
    human embryonic kidney
    NTCP
    sodium taurocholate-cotransporting polypeptide
    MDCK
    Madin-Darby canine kidney
    MPP
    1-methyl-4-phenylpyridinium
    CCK-8
    cholecystokinin octapeptide
    PAPS
    3′-phosphoadenosine-5′-phosphosulfate
    MDR1
    multidrug-resistant protein 1
    HPLC
    high-performance liquid chromatography
    FRT
    Flp recombination target
    PCR
    polymerase chain reaction
    RQ
    relative quantification
    BSP
    bromosulfophthalein
    PAH
    p-aminohippurate
    HBSS
    Hank's balanced salt solution
    Pc
    permeability coefficient
    GF-120918
    N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
    DHEAS
    dehydroepiandrosterone-3-sulfate
    OST
    organic-solute transporter.

  • 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 Liver 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) 1072-1082; DOI: https://doi.org/10.1124/dmd.109.031518

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Research ArticleArticle

Transporter Studies with the 3-O-Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Liver 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) 1072-1082; DOI: https://doi.org/10.1124/dmd.109.031518
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