{Reference Type}: Journal Article
{Title}: Assessing the degree of hepatic ischemia-reperfusion injury using PBPK modeling of sodium fluorescein disposition in ex vivo machine-perfused livers.
{Author}: Monti CE;Hong SK;Audi SH;Lee W;Joshi A;Terhune SS;Kim J;Dash RK;
{Journal}: Am J Physiol Gastrointest Liver Physiol
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 25
{Factor}: 4.871
{DOI}: 10.1152/ajpgi.00048.2024
{Abstract}: 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 multi-drug 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 6-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 3 unknown parameters. Finally, we fit the reduced model to each individual biological replicate SF time course with differing WIT and 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 30 min WIT. These studies provide the foundation for future studies investigating real-time assessment of liver viability during ex vivo MP.