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Research ArticleArticle

Hepatic Uptake in the Dog: Comparison of Uptake in Hepatocytes and Human Embryonic Kidney Cells Expressing Dog Organic Anion-Transporting Polypeptide 1B4

Alison J. Wilby, Kazuya Maeda, Paul F. Courtney, Yasuyuki Debori, Peter J. H. Webborn, Yoshiaki Kitamura, Hiroyuki Kusuhara, Rob J. Riley and Yuichi Sugiyama
Drug Metabolism and Disposition December 2011, 39 (12) 2361-2369; DOI: https://doi.org/10.1124/dmd.111.041814
Alison J. Wilby
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Kazuya Maeda
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Paul F. Courtney
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Yasuyuki Debori
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Peter J. H. Webborn
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Yoshiaki Kitamura
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Hiroyuki Kusuhara
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Rob J. Riley
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Yuichi Sugiyama
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Abstract

Although the dog is frequently used in pharmacological, pharmacokinetic, and drug safety studies, little is known about canine drug transporters. Dog organic anion-transporting polypeptide (Oatp1b4) has recently been cloned (Comp Biochem Physiol C Toxicol Pharmacol 151:393–399, 2010), but the contribution of Oatp1b4 to hepatic uptake has yet to be clarified. This study compares the transport characteristics of dog Oatp1b4 with those of human OATP1B1/1B3 and demonstrates the importance of Oatp1b4 in the uptake of anionic compounds in dog hepatocytes. Oatp1b4 is the predominant Oatp in dog liver with expression levels double and 30 times those of Oatp2b1 and Oatp1a2, respectively. Uptake of a range of typical OATP substrates by Oatp1b4-expressing HEK293 cells was compared with that in fresh dog hepatocytes. All compounds tested were transported by Oatp1b4 and uptake intrinsic clearance (CLint, uptake) in dog hepatocytes in sodium-free buffer was correlated significantly with CLint, uptake in Oatp1b4-expressing cells. Dog in vivo clearance for five substrates was predicted more accurately from CLint, uptake than from metabolic intrinsic clearance (CLint, met), indicating that uptake governs the overall in vivo hepatic clearance of these anionic compounds in dog. The substrate specificities of dog Oatp1b4 appear to be similar to those of human OATP1B1/OATP1B3, whereas the relative uptake clearance of substrates for Oatp1b4 correlate better with OATP1B3 than with the more abundant hepatic analog OATP1B1.

Footnotes

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

    doi:10.1124/dmd.111.041814.

  • ABBREVIATIONS:

    OATP/Oatp
    organic anion-transporting polypeptide
    BSP
    sulfobromophthalein
    E1S
    estrone-3-sulfate
    CCK-8
    cholecystokinin octapeptide
    HEK
    human embryonic kidney
    E2G
    estradiol 17β-glucuronide
    DHEAS
    dehydroepiandrosterone sulfate
    PCR
    polymerase chain reaction
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    MS/MS
    mass spectrometry.

  • Received July 15, 2011.
  • Accepted September 22, 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

UPTAKE IN DOG HEPATOCYTES AND Oatp1b4-EXPRESSING CELLS

Alison J. Wilby, Kazuya Maeda, Paul F. Courtney, Yasuyuki Debori, Peter J. H. Webborn, Yoshiaki Kitamura, Hiroyuki Kusuhara, Rob J. Riley and Yuichi Sugiyama
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2361-2369; DOI: https://doi.org/10.1124/dmd.111.041814

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Research ArticleArticle

UPTAKE IN DOG HEPATOCYTES AND Oatp1b4-EXPRESSING CELLS

Alison J. Wilby, Kazuya Maeda, Paul F. Courtney, Yasuyuki Debori, Peter J. H. Webborn, Yoshiaki Kitamura, Hiroyuki Kusuhara, Rob J. Riley and Yuichi Sugiyama
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2361-2369; DOI: https://doi.org/10.1124/dmd.111.041814
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