title: Liver Perfusion Modifies Gd-DTPA and Gd-BOPTA Hepatocyte Concentrations Through Transfer Clearances Across Sinusoidal Membranes.
abstract: OBJECTIVE
  Gadobenate dimeglumine (Gd-BOPTA) is a commercialised hepatobiliary contrast agent used during liver magnetic resonance imaging (MRI) to detect liver diseases. It enters into human hepatocytes through organic anion transporting polypeptides (OATP1B1/B3) and crosses the canalicular transporter multiple resistance-associated protein 2 (MRP2) to be excreted into bile canaliculi. Gd-BOPTA can return to sinusoids via the sinusoidal transporters MRP3/MRP4. Hepatocyte concentrations of Gd-BOPTA depend on three clearances: the sinusoidal clearance or volume of sinusoidal blood cleared of drugs per unit of time and two hepatocyte clearances (into bile canaliculi or back to sinusoids) or volume of hepatocytes cleared of drugs per unit of time in the respective liver compartments. The present study investigates whether changing liver blood flow modifies hepatocyte concentrations when plasma concentrations do not change.
  
  
  METHODS
  We perfused normal rat livers at various portal flow rates (24, 30, and 36 ml/min) with 200 µM Gd-BOPTA and measured sinusoidal clearances, hepatocyte clearances, and hepatocyte concentrations of Gd-BOPTA.
  
  
  RESULTS
  We showed that varying portal flow rates changes the sinusoidal clearance of Gd-BOPTA despite its low extraction ratio. Portal flow rates do not modify Gd-BOPTA clearance from hepatocytes into bile canaliculi but can change hepatocyte clearance back to sinusoids.
  
  
  CONCLUSIONS
  At a given perfused concentration, portal flow rates modify Gd-BOPTA hepatocyte concentrations, a result important to consider when interpreting liver imaging.
authors: Département de Radiologie, Hôpitaux Universitaires Paris Nord Val-de-Seine Beaujon, Clichy, France.
authors: Jean-Luc
authors: JL
authors: Daire
authors: Inserm U1149, Paris, France.
authors: Benjamin
authors: B
authors: Leporq
authors: Département de Radiologie, Hôpitaux Universitaires Paris Nord Val-de-Seine Beaujon, Clichy, France.|Inserm U1149, Paris, France.|University Paris Diderot, Paris, France.
authors: Valérie
authors: V
authors: Vilgrain
authors: Département de Radiologie, Hôpitaux Universitaires Paris Nord Val-de-Seine Beaujon, Clichy, France.|Inserm U1149, Paris, France.|University Paris Diderot, Paris, France.
authors: Bernard E
authors: BE
authors: Van Beers
authors: Département de Radiologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors: Sabine
authors: S
authors: Schmidt
authors: Inserm U1149, Paris, France. catherine.pastor@hcuge.ch.|University Paris Diderot, Paris, France. catherine.pastor@hcuge.ch.|Département d'Imagerie et des Sciences de l'Information, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil, 4, 1205, Geneva, Switzerland. catherine.pastor@hcuge.ch.
authors: Catherine M
authors: CM
authors: Pastor
mesh_terms: D000818:Animals; D001692:Biological Transport; D002196:Capillaries / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003287:Contrast Media / Q000493:pharmacokinetics*; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D026901:Membrane Transport Proteins / Q000378:metabolism; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D010477:Perfusion; D017207:Rats, Sprague-Dawley
chemical_list: D003287:Contrast Media; D026901:Membrane Transport Proteins; D009942:Organometallic Compounds; C064572:gadobenic acid; D008536:Meglumine; D019786:Gadolinium DTPA