title: Gadoxetate-enhanced MR imaging and compartmental modelling to assess hepatocyte bidirectional transport function in rats with advanced liver fibrosis.
abstract: OBJECTIVE
  Changes in the expression of hepatocyte membrane transporters in advanced fibrosis decrease the hepatic transport function of organic anions. The aim of our study was to assess if these changes can be evaluated with pharmacokinetic analysis of the hepatobiliary transport of the MR contrast agent gadoxetate.
  
  
  METHODS
  Dynamic gadoxetate-enhanced MRI was performed in 17 rats with advanced fibrosis and 8 normal rats. After deconvolution, hepatocyte three-compartmental analysis was performed to calculate the hepatocyte influx, biliary efflux and sinusoidal backflux rates. The expression of Oatp1a1, Mrp2 and Mrp3 organic anion membrane transporters was assessed with reverse transcription polymerase chain reaction.
  
  
  RESULTS
  In the rats with advanced fibrosis, the influx and efflux rates of gadoxetate decreased and the backflux rate increased significantly (p = 0.003, 0.041 and 0.010, respectively). Significant correlations were found between influx and Oatp1a1 expression (r = 0.78, p < 0.001), biliary efflux and Mrp2 (r = 0.50, p = 0.016) and sinusoidal backflux and Mrp3 (r = 0.61, p = 0.002).
  
  
  CONCLUSIONS
  These results show that changes in the bidirectional organic anion hepatocyte transport function in rats with advanced liver fibrosis can be assessed with compartmental analysis of gadoxetate-enhanced MRI.
  
  
  CONCLUSIONS
  • Expression of hepatocyte transporters is modified in rats with advanced liver fibrosis. • Kinetic parameters at gadoxetate-enhanced MRI are correlated with hepatocyte transporter expression. • Hepatocyte transport function can be assessed with compartmental analysis of gadoxetate-enhanced MRI. • Compartmental analysis of gadoxetate-enhanced MRI might provide biomarkers in advanced liver fibrosis.
authors.affiliation: Laboratory of Imaging Biomarkers, UMR1149 Inserm, University Paris Diderot, Sorbonne Paris Cité, Hôpital Beaujon, 100 boulevard du général Leclerc, 92110, Clichy, France. giraudeau.celine@hotmail.fr.
authors.forename: Céline
authors.initials: C
authors.lastname: Giraudeau
authors.affiliation: Laboratory of Imaging Biomarkers, UMR1149 Inserm, University Paris Diderot, Sorbonne Paris Cité, Hôpital Beaujon, 100 boulevard du général Leclerc, 92110, Clichy, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leporq
authors.affiliation: Laboratory of Imaging Biomarkers, UMR1149 Inserm, University Paris Diderot, Sorbonne Paris Cité, Hôpital Beaujon, 100 boulevard du général Leclerc, 92110, Clichy, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Doblas
authors.affiliation: Laboratory of Imaging Biomarkers, UMR1149 Inserm, University Paris Diderot, Sorbonne Paris Cité, Hôpital Beaujon, 100 boulevard du général Leclerc, 92110, Clichy, France.|Department of Radiology, Beaujon University Hospital Paris Nord, Clichy, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Lagadec
authors.affiliation: Laboratory of Imaging Biomarkers, UMR1149 Inserm, University Paris Diderot, Sorbonne Paris Cité, Hôpital Beaujon, 100 boulevard du général Leclerc, 92110, Clichy, France.|Département d'imagerie et des sciences de l'information médicale, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Pastor
authors.affiliation: Laboratory of Imaging Biomarkers, UMR1149 Inserm, University Paris Diderot, Sorbonne Paris Cité, Hôpital Beaujon, 100 boulevard du général Leclerc, 92110, Clichy, France.|Department of Radiology, Beaujon University Hospital Paris Nord, Clichy, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Daire
authors.affiliation: Laboratory of Imaging Biomarkers, UMR1149 Inserm, University Paris Diderot, Sorbonne Paris Cité, Hôpital Beaujon, 100 boulevard du général Leclerc, 92110, Clichy, France.|Department of Radiology, Beaujon University Hospital Paris Nord, Clichy, France.
authors.forename: Bernard E
authors.initials: BE
authors.lastname: Van Beers
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000000981:diagnostic imaging* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D016022:Case-Control Studies; D003287:Contrast Media; D004195:Disease Models, Animal; D019786:Gadolinium DTPA; D022781:Hepatocytes / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D008099:Liver / Q000000981:diagnostic imaging* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015415:Biomarkers; D003287:Contrast Media; D026901:Membrane Transport Proteins; C073590:gadolinium ethoxybenzyl DTPA; D002251:Carbon Tetrachloride; D019786:Gadolinium DTPA
keywords: Compartmental modeling; Expression of membrane transporter; Gadoxetate-enhanced MRI; Hepatocyte transport function; Rat liver fibrosis