title: Advanced fibrosis: Correlation between pharmacokinetic parameters at dynamic gadoxetate-enhanced MR imaging and hepatocyte organic anion transporter expression in rat liver.
abstract: OBJECTIVE
  To compare the value of enhancement and pharmacokinetic parameters measured at dynamic gadoxetate-enhanced magnetic resonance (MR) imaging in determining hepatic organic anion transporter expression in control rats and rats with advanced liver fibrosis.
  
  
  METHODS
  Institutional animal review board approval was received before the study began. Advanced liver fibrosis was created in rats by means of carbon tetrachloride injections over an 8-week period. In 17 rats with liver fibrosis and eight control rats, dynamic gadoxetate-enhanced MR images of the liver were obtained during 1 hour after injection of 0.025 mmol gadoxetate per kilogram of body weight. Enhancement parameters (maximum enhancement [Emax], time to peak [Tmax], and elimination half-life) were measured on enhancement-versus-time curves, and pharmacokinetic parameters (hepatic extraction fraction [HEF] and mean residence time [MRT]) were obtained by means of deconvolution analysis of the concentration-versus-time curves in the liver and the portal vein. The parameters were correlated at simple and multiple regression analysis with the expression of the hepatic anion uptake transporter organic anion-transporting polypeptide 1A1 (Oatp1a1), the hepatobiliary transporter multidrug resistance-associated protein 2 (Mrp2), and the backflux transporter Mrp4, as determined with reverse transcription polymerase chain reaction.
  
  
  RESULTS
  In rats with advanced liver fibrosis, the Emax, Tmax, HEF, and MRT decreased significantly relative to those in control rats, whereas the elimination half-life increased significantly. The enhancement and pharmacokinetic parameters correlated significantly with the expression of the transporters at simple regression analysis. At multiple regression analysis, HEF was the only parameter that was significantly associated with the expression of Oatp1a1 and Mrp2 (P < .001, r = 0.74 and P < .001, r = 0.70, respectively).
  
  
  CONCLUSIONS
  The pharmacokinetic parameter HEF at dynamic gadoxetate-enhanced MR imaging is independently correlated with hepatic organic anion transporter expression.
authors.affiliation: From the Laboratory of Physiological and Molecular Imaging of the Abdomen and Department of Radiology, DHU Unity, University Paris Diderot, Sorbonne Paris Cité, INSERM UMR 1149 Center of Research on Inflammation, Beaujon University Hospital, 100 Boulevard du Général Leclerc, 92110 Clichy, France (M.L., S.D., C.G., M.R., S.A.L., C.M.P., V.V., J.L.D., B.E.V.B.); Department of Hepatology, DHU Unity, University Paris Diderot, INSERM UMR 1149, Beaujon University Hospital, Clichy, France (M.F., R.M.); Department of Pathology, DHU Unity, University Paris Diderot, INSERM UMR 1149, Beaujon University Hospital, Clichy, France (V.P.); and Department of Medical Imaging, University Hospitals of Geneva, Geneva, Switzerland (C.M.P.).
authors.forename: Matthieu
authors.initials: M
authors.lastname: Lagadec
authors.forename: Sabrina
authors.initials: S
authors.lastname: Doblas
authors.forename: Céline
authors.initials: C
authors.lastname: Giraudeau
authors.forename: Maxime
authors.initials: M
authors.lastname: Ronot
authors.forename: Simon A
authors.initials: SA
authors.lastname: Lambert
authors.forename: Magali
authors.initials: M
authors.lastname: Fasseu
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
authors.forename: Richard
authors.initials: R
authors.lastname: Moreau
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Pastor
authors.forename: Valérie
authors.initials: V
authors.lastname: Vilgrain
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Daire
authors.forename: Bernard E
authors.initials: BE
authors.lastname: Van Beers
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000493:pharmacokinetics*; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000175:diagnosis* / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index
chemical_list: D003287:Contrast Media; D019786:Gadolinium DTPA; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; C073590:gadolinium ethoxybenzyl DTPA