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Research ArticleArticle

Hepatocyte-Specific Deletion of EGFR in Mice Reduces Hepatic Abcg2 Transport Activity Measured by [11C]erlotinib and Positron Emission Tomography

Alexander Traxl, Karin Komposch, Elisabeth Glitzner, Thomas Wanek, Severin Mairinger, Oliver Langer and Maria Sibilia
Drug Metabolism and Disposition October 2017, 45 (10) 1093-1100; DOI: https://doi.org/10.1124/dmd.117.077081
Alexander Traxl
Center for Health and Bioresources, Biomedical Systems, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria (A.T., T.W., S.M., O.L.); Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center (K.K., E.G., M.S.); Department of Clinical Pharmacology (O.L.) and Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine (O.L.), Medical University of Vienna, Vienna, Austria
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Karin Komposch
Center for Health and Bioresources, Biomedical Systems, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria (A.T., T.W., S.M., O.L.); Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center (K.K., E.G., M.S.); Department of Clinical Pharmacology (O.L.) and Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine (O.L.), Medical University of Vienna, Vienna, Austria
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Elisabeth Glitzner
Center for Health and Bioresources, Biomedical Systems, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria (A.T., T.W., S.M., O.L.); Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center (K.K., E.G., M.S.); Department of Clinical Pharmacology (O.L.) and Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine (O.L.), Medical University of Vienna, Vienna, Austria
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Thomas Wanek
Center for Health and Bioresources, Biomedical Systems, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria (A.T., T.W., S.M., O.L.); Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center (K.K., E.G., M.S.); Department of Clinical Pharmacology (O.L.) and Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine (O.L.), Medical University of Vienna, Vienna, Austria
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Severin Mairinger
Center for Health and Bioresources, Biomedical Systems, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria (A.T., T.W., S.M., O.L.); Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center (K.K., E.G., M.S.); Department of Clinical Pharmacology (O.L.) and Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine (O.L.), Medical University of Vienna, Vienna, Austria
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Oliver Langer
Center for Health and Bioresources, Biomedical Systems, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria (A.T., T.W., S.M., O.L.); Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center (K.K., E.G., M.S.); Department of Clinical Pharmacology (O.L.) and Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine (O.L.), Medical University of Vienna, Vienna, Austria
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Maria Sibilia
Center for Health and Bioresources, Biomedical Systems, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria (A.T., T.W., S.M., O.L.); Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center (K.K., E.G., M.S.); Department of Clinical Pharmacology (O.L.) and Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine (O.L.), Medical University of Vienna, Vienna, Austria
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Abstract

The epidermal growth factor receptor (EGFR) regulates cellular expression levels of breast cancer resistance protein (humans: ABCG2, rodents: Abcg2) via its downstream signaling pathways. Drugs that inhibit EGFR signaling (e.g., tyrosine kinase inhibitors, antibodies) may lead to ABCG2-mediated drug-drug interactions (DDIs) by changing the disposition of concomitantly administered ABCG2 substrate drugs. In this study, we used positron emission tomography and magnetic resonance imaging to compare disposition of the model Abcg2 substrate [11C]erlotinib in a mouse model of hepatocyte-specific deletion of EGFR (EGFR∆hep mice, n = 5) with EGFRfl/fl control mice (n = 6), which have normal EGFR expression levels in all tissues. Integration plot analysis was used to estimate the rate constants for transfer of radioactivity from the liver into bile (kbile) and from the kidney into urine (kurine). EGFR∆hep mice showed significantly lower radioactivity concentrations in the intestine (1.6-fold) and higher radioactivity concentrations in the urinary bladder (3.2-fold) compared with EGFRfl/fl mice. Kbile was significantly decreased (3.0-fold) in EGFR∆hep mice, whereas kurine was by 2.2-fold increased. Western blot analysis of liver tissue confirmed deletion of EGFR and showed significant decreases in Abcg2 and increases in P-glycoprotein (Abcb1a/b) expression levels in EGFR∆hep versus EGFRfl/fl mice. Our data show that EGFR deletion in hepatocytes leads to a reduction in Abcg2-mediated hepatobiliary clearance of a probe substrate accompanied by a shift to renal excretion of the drug, which raises the possibility that EGFR-inhibiting drugs may cause ABCG2-mediated DDIs.

Footnotes

    • Received June 20, 2017.
    • Accepted August 4, 2017.
  • ↵1 A.T., E.G., and K.K. contributed equally to this study.

  • ↵2 O.L. and M.S. had equal responsibility for this study.

  • This work was supported by the Austrian Science Fund (FWF) [Grants F3518-B20, F3513-B20] and by the Lower Austria Corporation for Research and Education (NFB) [Grants LS12-006, LS15-003].

  • https://doi.org/10.1124/dmd.117.077081.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 45 (10)
Drug Metabolism and Disposition
Vol. 45, Issue 10
1 Oct 2017
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Research ArticleArticle

EGFR and Hepatic Abcg2 Transport Activity

Alexander Traxl, Karin Komposch, Elisabeth Glitzner, Thomas Wanek, Severin Mairinger, Oliver Langer and Maria Sibilia
Drug Metabolism and Disposition October 1, 2017, 45 (10) 1093-1100; DOI: https://doi.org/10.1124/dmd.117.077081

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Research ArticleArticle

EGFR and Hepatic Abcg2 Transport Activity

Alexander Traxl, Karin Komposch, Elisabeth Glitzner, Thomas Wanek, Severin Mairinger, Oliver Langer and Maria Sibilia
Drug Metabolism and Disposition October 1, 2017, 45 (10) 1093-1100; DOI: https://doi.org/10.1124/dmd.117.077081
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