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