RT Journal Article SR Electronic T1 Hepatocyte-specific deletion of EGFR in mice reduces hepatic Abcg2 transport activity measured with [11C]erlotinib and positron emission tomography JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.117.077081 DO 10.1124/dmd.117.077081 A1 Alexander Traxl A1 Karin Komposch A1 Elisabeth Glitzner A1 Thomas Wanek A1 Severin Mairinger A1 Oliver Langer A1 Maria Sibilia YR 2017 UL http://dmd.aspetjournals.org/content/early/2017/08/08/dmd.117.077081.abstract AB 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 disposition of concomitantly administered ABCG2 substrate drugs. In this study we used positron emission tomography (PET)/magnetic resonance (MR) imaging to compare disposition of the model Abcg2 substrate [11C]erlotinib in a mouse model of hepatocyte-specific deletion of EGFR (EGFRΔhep 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 liver into bile (kbile) and from kidney into urine (kurine). EGFRΔhep mice showed significantly lower radioactivity concentrations in the intestine (1.6-fold) and higher radioactivity concentrations in the urinary bladder (3.2-fold) as compared to EGFRfl/fl mice. Kbile was significantly decreased (3.0-fold) in EGFRΔhep 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 EGFRΔhep vs. 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.