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.
Keywords: liver, hepatic clearance, biliary excretion,
transplantation