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Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
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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.