Assessing the degree of hepatic ischemia-reperfusion injury using physiologically based pharmacokinetic modeling of sodium fluorescein disposition in ex vivo machine-perfused livers. Am J Physiol Gastrointest Liver Physiol 2024 Sep 01;327(3):G424-G437
Date
06/25/2024Pubmed ID
38917324Pubmed Central ID
PMC11427087DOI
10.1152/ajpgi.00048.2024Scopus ID
2-s2.0-85202790681 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
Ischemia-reperfusion injury (IRI) is an intrinsic risk associated with liver transplantation. Ex vivo hepatic machine perfusion (MP) is an emerging organ preservation technique that can mitigate IRI, especially in livers subjected to prolonged warm ischemia time (WIT). However, a method to quantify the biological response to WIT during MP has not been established. Previous studies used physiologically based pharmacokinetic (PBPK) modeling to demonstrate that a decrease in hepatic transport and biliary excretion of the tracer molecule sodium fluorescein (SF) could correlate with increasing WIT in situ. Furthermore, these studies proposed intracellular sequestration of the hepatocyte canalicular membrane transporter multidrug resistance-associated protein 2 (MRP2) leading to decreased MRP2 activity (maximal transport velocity; Vmax) as the potential mechanism for decreased biliary SF excretion. We adapted an extant PBPK model to account for ex vivo hepatic MP and fit a six-parameter version of this model to control time-course measurements of SF in MP perfusate and bile. We then identified parameters whose values were likely insensitive to changes in WIT and fixed them to generate a reduced model with only three unknown parameters. Finally, we fit the reduced model to each individual biological replicate SF time course with differing WIT, found the mean estimated value for each parameter, and compared them using a one-way ANOVA. We demonstrated that there was a significant decrease in the estimated value of Vmax for MRP2 at the 30-min WIT. These studies provide the foundation for future studies investigating real-time assessment of liver viability during ex vivo MP.NEW & NOTEWORTHY We developed a computational model of sodium fluorescein (SF) biliary excretion in ex vivo machine perfusion and used this model to assess changes in model parameters associated with the activity of MRP2, a hepatocyte membrane transporter, in response to increasing warm ischemia time. We found a significant decrease in the parameter value describing MRP2 activity, consistent with a role of decreased MRP2 function in ischemia-reperfusion injury leading to decreased secretion of SF into bile.
Author List
Monti CE, Hong SK, Audi SH, Lee W, Joshi A, Terhune SS, Kim J, Dash RKAuthors
Said Audi PhD Professor in the Biomedical Engineering department at Marquette UniversityRanjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
Amit Joshi PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
Whayoung Lee MD Assistant Professor in the Pathology and Laboratory Medicine department at Medical College of Wisconsin
Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
ATP-Binding Cassette TransportersAnimals
Bile
Fluorescein
Hepatobiliary Elimination
Liver
Liver Transplantation
Models, Biological
Organ Preservation
Perfusion
Reperfusion Injury
Warm Ischemia
