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Liver Perfusion Modifies Gd-DTPA and Gd-BOPTA Hepatocyte Concentrations Through Transfer Clearances Across Sinusoidal Membranes

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

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.

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Authors and Affiliations

  1. Département de Radiologie, Hôpitaux Universitaires Paris Nord Val-de-Seine Beaujon, Clichy, France

    Jean-Luc Daire, Valérie Vilgrain & Bernard E. Van Beers

  2. Inserm U1149, Paris, France

    Benjamin Leporq, Valérie Vilgrain, Bernard E. Van Beers & Catherine M. Pastor

  3. University Paris Diderot, Paris, France

    Valérie Vilgrain, Bernard E. Van Beers & Catherine M. Pastor

  4. Département de Radiologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    Sabine Schmidt

  5. Département d’Imagerie et des Sciences de l’Information, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil, 4, 1205, Geneva, Switzerland

    Catherine M. Pastor

Authors
  1. Jean-Luc Daire
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  2. Benjamin Leporq
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  3. Valérie Vilgrain
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  4. Bernard E. Van Beers
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  5. Sabine Schmidt
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  6. Catherine M. Pastor
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Corresponding author

Correspondence to Catherine M. Pastor.

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Funding

This study was funded by the Swiss National Foundation (Grant N° 126030).

Conflict of interest

Jean-Luc Daire, Benjamin Leporq, Valérie Vilgrain, Bernard E Van Beers, Sabine Schmidt, and Catherine M Pastor have no conflicts of interest to declare.

Ethical approval

Study approved by the Geneva animal welfare committee and veterinary office. All institutional and national guidelines for the care of the laboratory animals were followed.

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Daire, JL., Leporq, B., Vilgrain, V. et al. Liver Perfusion Modifies Gd-DTPA and Gd-BOPTA Hepatocyte Concentrations Through Transfer Clearances Across Sinusoidal Membranes. Eur J Drug Metab Pharmacokinet 42, 657–667 (2017). https://doi.org/10.1007/s13318-016-0382-x

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  • DOI: https://doi.org/10.1007/s13318-016-0382-x

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