Novel explanted human liver model to assess hepatic extraction, biliary excretion and transporter function.

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 assess hepatic extraction, clearance, biliary excretion and drug-drug interaction. 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, NMP was initiated. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin and furosemide; OATP1B1/1B3, Pgp, BCRP and OCT1 model compounds) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with perpetrator drugs to study relevant drug-drug interactions. The explanted livers showed good viability and functionality during 360 minutes of NMP. Hepatic extraction ratios close to in vivo reported values were measured. Hepatic clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in Cmax of 11.50 and 2.89 times, respectively, compared to non-cirrhotic livers. No major differences were observed for metformin and furosemide. Interaction of rosuvastatin or digoxin with perpetrator drugs were more pronounced in non-cirrhotic livers compared to cirrhotic livers. Our results demonstrated that NMP of human diseased explanted livers is an excellent model to assess hepatic extraction, clearance, biliary excretion and drug-drug interaction. Gaining insight into pharmacokinetic profiles of OATP1B1/1B3, Pgp, BCRP and OCT1 model compounds is a first step towards studying transporter functions in diseased liver.