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Abstract: SA-PO272

Optimized Normothermic Machine Perfusion of Kidney, Liver, and Combined Liver-Kidney to Predict Human Pharmacokinetics

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Van Koppen, Arianne, TNO, Leiden, South Holland, Netherlands
  • Stoop, Reinout, TNO, Leiden, South Holland, Netherlands
Background

Robust translational models are key to predict the intestinal absorption, hepatic clearance (metabolic and biliary) and renal clearance of compounds. Ex vivo normothermic machine perfusion (NMP) of whole organs is a promising tool, especially when combined with physiologically-based pharmacokinetic (PBPK) modeling to reliably predict human exposure levels. We aimed to optimize organ functioning during NMP and to demonstrate prediction of ADME data of model drugs (rosuvastatin, digoxin, metformin and furosemide) of liver and kidney combined with ex vivo intestinal absorption studies and PBPK modeling to predict the drug PK profile in humans.

Methods

Three ex vivo models were applied using porcine organs 1) the inTESTine system (n=3) to study apical to basolateral intestinal transport, 2) normothermic machine perfusion of ex vivo liver (n=3) to determine hepatic uptake, clearance and biliary excretion and 3) normothermic machine perfusion of ex vivo kidney (n=3) to determine renal clearance and urinary excretion.

Results

Intestinal absorption of digoxin and rosuvastatin were limited. Perfused porcine livers rapidly cleared rosuvastatin and digoxin from perfusate (hepatic extraction ratio of 0.82 and 0.31). Compounds were traced in bile after 10 min (rosuvastatin; 23%, digoxin; 51%, metformin and furosemide; ~0.2%). Renal excretion of rosuvastatin and digoxin was low, but high for furosemide and metformin (>90%).

Conclusion

NMP can be optimized to sustain organ functionality during perfusion. The combination of ex vivo gut, liver and kidney models with a generic PBPK model is a unique and powerful combination to predict ADME profile of (new) drugs, including the possibility to calculate the fraction that undergoes enterohepatic circulation. Future research is aimed at studying drug-drug interactions and the effects of disease processes.