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Normothermic perfusion of cirrhotic and non-cirrhotic explanted human livers: applicability to study drug pharmacokinetics
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  • Lianne Stevens,
  • Jeroen Dubbeld,
  • Jason Doppenberg,
  • Bart van Hoek,
  • Aswin Menke,
  • Joanne Donkers,
  • Abdulnaser Alsharaa,
  • Arjan de Vries,
  • Wouter Vaes,
  • Catherijne Knibbe,
  • Evita van de Steeg,
  • Ian Alwayn
Lianne Stevens
Leiden University Medical Center

Corresponding Author:l.j.stevens@lumc.nl

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Jeroen Dubbeld
Leiden University Medical Center
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Jason Doppenberg
Leiden University Medical Center
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Bart van Hoek
Leiden University Medical Center
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Aswin Menke
Netherlands Organization for Applied Scientific Research
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Joanne Donkers
TNO
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Abdulnaser Alsharaa
TNO
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Arjan de Vries
TNO
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Wouter Vaes
TNO
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Catherijne Knibbe
Leiden/Amsterdam Center for Drug Research
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Evita van de Steeg
TNO
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Ian Alwayn
Leiden University Medical Center
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Abstract

Background and Purpose: Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can be used to investigate hepatic first-pass, clearance, biliary excretion and drug-drug interactions. Experimental approach: Eleven livers were included in the study, seven with a cirrhotic and four with a non-cirrhotic disease background. After explantation of the diseased liver, the liver artery and portal vein were reconstructed followed by NMP. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin and furosemide) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with drug inhibitors to study relevant drug-drug interactions. Key results: The explanted livers showed good viability and functionality after explantation and 360 minutes of NMP. Hepatic first-pass and clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in Cmax of 10.03 and 2.89 times, respectively, compared to non-cirrhotic livers. No major differences were observed for metformin and furosemide. Drug-drug interaction of rosuvastatin or digoxin with inhibitors were more pronounced in non-cirrhotic livers compared to cirrhotic livers. Conclusions and Implications: Our results demonstrated that explanted cirrhotic and non-cirrhotic livers were suitable for NMP and we demonstrated the applicability to study hepatic first pass, clearance, biliary excretion and drug-drug interaction. This model can be applied in a variety of research settings for hepatology, transplantation and pharmacology