Hepatocyte-Specific Deletion of EGFR in Mice Reduces Hepatic Abcg2 Transport Activity Measured by [11C]erlotinib and Positron Emission Tomography.
Drug Metab Dispos
; 45(10): 1093-1100, 2017 10.
Article
em En
| MEDLINE
| ID: mdl-28790147
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hepatócitos
/
Receptores ErbB
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Cloridrato de Erlotinib
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Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Drug Metab Dispos
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2017
Tipo de documento:
Article