Jean-Luc Daire1, Benjamin Leporq2, Valérie Vilgrain1,2,3, Bernard E Van Beers1,2,3, Sabine Schmidt4, Catherine M Pastor5,6,7. 1. Département de Radiologie, Hôpitaux Universitaires Paris Nord Val-de-Seine Beaujon, Clichy, France. 2. Inserm U1149, Paris, France. 3. University Paris Diderot, Paris, France. 4. Département de Radiologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 5. Inserm U1149, Paris, France. catherine.pastor@hcuge.ch. 6. University Paris Diderot, Paris, France. catherine.pastor@hcuge.ch. 7. 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.
Abstract
BACKGROUND AND OBJECTIVES: 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. CONCLUSION: At a given perfused concentration, portal flow rates modify Gd-BOPTA hepatocyte concentrations, a result important to consider when interpreting liver imaging.
BACKGROUND AND OBJECTIVES: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. CONCLUSION: At a given perfused concentration, portal flow rates modify Gd-BOPTA hepatocyte concentrations, a result important to consider when interpreting liver imaging.
Authors: K L R Brouwer; D Keppler; K A Hoffmaster; D A J Bow; Y Cheng; Y Lai; J E Palm; B Stieger; R Evers Journal: Clin Pharmacol Ther Date: 2013-04-10 Impact factor: 6.875
Authors: Corinne Planchamp; Gerd J Beyer; Daniel O Slosman; François Terrier; Catherine M Pastor Journal: Appl Radiat Isot Date: 2005-01-07 Impact factor: 1.513
Authors: Sara Vander Borght; Louis Libbrecht; Hans Blokzijl; Klaas Nico Faber; Han Moshage; Raymond Aerts; Werner Van Steenbergen; Peter L Jansen; Valeer J Desmet; Tania A Roskams Journal: J Pathol Date: 2005-12 Impact factor: 7.996