Céline Giraudeau1, Benjamin Leporq2, Sabrina Doblas2, Matthieu Lagadec2,3, Catherine M Pastor2,4, Jean-Luc Daire2,3, Bernard E Van Beers2,3. 1. 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. 2. Laboratory of Imaging Biomarkers, UMR1149 Inserm, University Paris Diderot, Sorbonne Paris Cité, Hôpital Beaujon, 100 boulevard du général Leclerc, 92110, Clichy, France. 3. Department of Radiology, Beaujon University Hospital Paris Nord, Clichy, France. 4. Département d'imagerie et des sciences de l'information médicale, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
Abstract
OBJECTIVES: 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). CONCLUSION: 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. KEY POINTS: • 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.
OBJECTIVES: 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). CONCLUSION: 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. KEY POINTS: • 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.
Entities:
Keywords:
Compartmental modeling; Expression of membrane transporter; Gadoxetate-enhanced MRI; Hepatocyte transport function; Rat liver fibrosis
Authors: Kathleen M Giacomini; Shiew-Mei Huang; Donald J Tweedie; Leslie Z Benet; Kim L R Brouwer; Xiaoyan Chu; Amber Dahlin; Raymond Evers; Volker Fischer; Kathleen M Hillgren; Keith A Hoffmaster; Toshihisa Ishikawa; Dietrich Keppler; Richard B Kim; Caroline A Lee; Mikko Niemi; Joseph W Polli; Yuichi Sugiyama; Peter W Swaan; Joseph A Ware; Stephen H Wright; Sook Wah Yee; Maciej J Zamek-Gliszczynski; Lei Zhang Journal: Nat Rev Drug Discov Date: 2010-03 Impact factor: 84.694
Authors: Reeta L Veteläinen; Roelof J Bennink; Kora de Bruin; Arlène van Vliet; Thomas M van Gulik Journal: Eur J Nucl Med Mol Imaging Date: 2006-10 Impact factor: 9.236
Authors: Ahmed Ba-Ssalamah; Nina Bastati; Andreas Wibmer; Romana Fragner; Jacqueline C Hodge; Michael Trauner; Christian J Herold; Mustafa R Bashir; Bernard E Van Beers Journal: J Magn Reson Imaging Date: 2016-11-08 Impact factor: 4.813
Authors: Tobias Heye; Elmar M Merkle; Caecilia S Reiner; Matthew S Davenport; Jeffrey J Horvath; Sebastian Feuerlein; Steven R Breault; Peter Gall; Mustafa R Bashir; Brian M Dale; Atilla P Kiraly; Daniel T Boll Journal: Radiology Date: 2012-12-06 Impact factor: 11.105
Authors: Dorela D Shuboni-Mulligan; Maciej Parys; Barbara Blanco-Fernandez; Christiane L Mallett; Regina Schnegelberger; Marilia Takada; Shatadru Chakravarty; Bruno Hagenbuch; Erik M Shapiro Journal: Diabetes Date: 2018-11-28 Impact factor: 9.461
Authors: Anastassia Karageorgis; Stephen C Lenhard; Brittany Yerby; Mikael F Forsgren; Serguei Liachenko; Edvin Johansson; Mark A Pilling; Richard A Peterson; Xi Yang; Dominic P Williams; Sharon E Ungersma; Ryan E Morgan; Kim L R Brouwer; Beat M Jucker; Paul D Hockings Journal: PLoS One Date: 2018-05-17 Impact factor: 3.240
Authors: Sabina Ziemian; Claudia Green; Steven Sourbron; Gregor Jost; Gunnar Schütz; Catherine D G Hines Journal: NMR Biomed Date: 2020-08-26 Impact factor: 4.044
Authors: Daniel Scotcher; Nicola Melillo; Sirisha Tadimalla; Adam S Darwich; Sabina Ziemian; Kayode Ogungbenro; Gunnar Schütz; Steven Sourbron; Aleksandra Galetin Journal: Mol Pharm Date: 2021-07-20 Impact factor: 4.939