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Rapid CommunicationShort Communication

Hepatic Uptake of the Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA: Role of Human Organic Anion Transporters

Mirko Leonhardt, Markus Keiser, Stefan Oswald, Jens Kühn, Jia Jia, Markus Grube, Heyo K. Kroemer, Werner Siegmund and Werner Weitschies
Drug Metabolism and Disposition July 2010, 38 (7) 1024-1028; DOI: https://doi.org/10.1124/dmd.110.032862
Mirko Leonhardt
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Markus Keiser
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Stefan Oswald
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Jens Kühn
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Jia Jia
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Markus Grube
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Heyo K. Kroemer
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Werner Siegmund
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Werner Weitschies
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Abstract

Contrast-enhancing magnetic resonance imaging with the liver-specific agent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) has been shown to improve the detection rate of focal lesions. There is evidence from preclinical studies that multidrug organic anion transporters are involved in hepatic uptake of Gd-EOB-DTPA. Therefore, we evaluated affinity of the contrast agent to human organic anion-transporting polypeptides (OATP1B1, OATP1B3, OATP2B1) and to the Na+/taurocholate cotransporting polypeptide (NTCP) using stable transfected human embryonic kidney (HEK) 293 cells. In competition assays, Gd-EOB-DTPA inhibited the uptake of bromosulfophthalein (BSP) by OATP1B1 (IC50 = 0.6 mM) and OATP1B3 (IC50 = 0.4 mM). In comparison, the IC50 values for rifampicin were 11.9 (OATP1B1), 1.4 (OATP1B3), and 80.5 μM (OATP2B1), respectively. Uptake of BSP by OATP2B1, uptake of taurocholic acid by NTCP, and viability of all HEK cells were not influenced by Gd-EOB-DTPA in concentrations up to 10 mM. In uptake assays using a new liquid chromatography-tandem mass spectrometry method for quantification, Gd-EOB-DTPA was a substrate for OATP1B1 (Km = 0.7 mM, Vmax = 10.5 pmol/mg × min), OATP1B3 (Km = 4.1 mM, Vmax = 22.7 pmol/mg × min), and NTCP (Km = 0.04 mM, Vmax = 1.4 pmol/mg × min). The uptake by OATP2B1 was not different from the vector control. In conclusion, Gd-EOB-DTPA is a substrate of the liver-specific OATP1B1, OATP1B3, and NTCP.

Footnotes

  • This work was supported by the German Federal Ministry of Education and Research [Grants BMBF InnoProfile 03IP612, BMBF 0314107].

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

    doi:10.1124/dmd.110.032862.

  • ABBREVIATIONS:

    MRI
    magnetic resonance imaging
    Gd-EOB-DTPA
    gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid
    NTCP
    Na+/taurocholate cotransporting polypeptide
    OATP
    organic anion-transporting polypeptide
    BSP
    bromosulfophthalein
    HEK
    human embryonic kidney
    TA
    taurocholic acid
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    MDCK
    Madin-Darby canine kidney
    cRNA
    complementary RNA.

  • Received February 16, 2010.
  • Accepted April 16, 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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Rapid CommunicationShort Communication

Hepatic Uptake of the Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA: Role of Human Organic Anion Transporters

Mirko Leonhardt, Markus Keiser, Stefan Oswald, Jens Kühn, Jia Jia, Markus Grube, Heyo K. Kroemer, Werner Siegmund and Werner Weitschies
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1024-1028; DOI: https://doi.org/10.1124/dmd.110.032862

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Rapid CommunicationShort Communication

Hepatic Uptake of the Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA: Role of Human Organic Anion Transporters

Mirko Leonhardt, Markus Keiser, Stefan Oswald, Jens Kühn, Jia Jia, Markus Grube, Heyo K. Kroemer, Werner Siegmund and Werner Weitschies
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1024-1028; DOI: https://doi.org/10.1124/dmd.110.032862
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