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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
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Novel Explanted Human Liver Model to Assess Hepatic Extraction, Biliary Excretion and Transporter Function
Lianne J Stevens1,2,3, Jeroen Dubbeld1,2, Jason B Doppenberg2
1Department of Surgery, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Clinical Pharmacology and Therapeutics
|April 12, 2023
Summary
This study developed a human liver model using machine perfusion to study drug interactions in diseased livers. Cirrhosis significantly impacted drug clearance, highlighting the model
Area of Science:
- Hepatology and Pharmacology
- Drug Metabolism and Pharmacokinetics
- Biomedical Engineering
Background:
- Realistic models for predicting hepatobiliary processes in health and disease are currently lacking.
- Understanding drug behavior in diseased livers is crucial for effective treatment and drug development.
Purpose of the Study:
- To develop a physiologically relevant human liver model using normothermic machine perfusion (NMP) of explanted diseased livers.
- To assess hepatic extraction, clearance, biliary excretion, and drug-drug interactions (DDIs) in cirrhotic and noncirrhotic human livers.
- To investigate the impact of cirrhosis on the pharmacokinetics of specific drug transporter substrates.
Main Methods:
- Normothermic machine perfusion (NMP) of eleven explanted human livers (seven cirrhotic, four noncirrhotic) for 360 minutes.
- Administration of a drug cocktail (rosuvastatin, digoxin, metformin, furosemide) and subsequent co-administration with perpetrator drugs to study DDIs.
- Measurement of hepatic extraction, clearance, and pharmacokinetic parameters.
Main Results:
- Explanted livers maintained viability and functionality during NMP, with measured hepatic extraction ratios close to in vivo values.
- Cirrhosis significantly increased maximum plasma concentration (Cmax) for rosuvastatin (11.50-fold) and digoxin (2.89-fold) compared to noncirrhotic livers.
- Drug-drug interactions were more pronounced for rosuvastatin and digoxin in noncirrhotic livers than in cirrhotic livers.
Conclusions:
- Normothermic machine perfusion of human diseased explanted livers provides an excellent model for assessing hepatic drug disposition and DDIs.
- This model offers valuable insights into transporter functions and drug behavior in diseased liver conditions.
- The findings underscore the significant impact of cirrhosis on drug pharmacokinetics and highlight the need for personalized drug strategies.
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