Physiologically-Based Pharmacokinetic Modeling of Blood Clearance of Liver Fluorescent Markers for the Assessment of the Degree of Hepatic Ischemia-Reperfusion Injury

TL;DR

This study develops a physiologically-based pharmacokinetic model to quantify how liver ischemia-reperfusion injury affects blood clearance of fluorescent markers, potentially improving assessment of liver injury during transplantation.

Contribution

The paper introduces a novel PBPK model specifically for sodium fluorescein clearance via bile, linking it to hepatic MRP2 activity and IRI severity.

Findings

SF bile concentration is highly sensitive to MRP2 activity changes

The PBPK model can quantify IRI effects on liver function

Simulations suggest potential for non-invasive IRI assessment

Abstract

During liver transplantation, ischemia-reperfusion injury (IRI) is inevitable and decreases the overall success of the surgery. While guidelines exist, there is no reliable way to quantitatively assess the degree of IRI present in the liver. Our recent study has shown a correlation between the bile-to-plasma ratio of FDA-approved sodium fluorescein (SF) and the degree of hepatic IRI, presumably due to IRI-induced decrease in the activity of the hepatic multidrug resistance-associated protein 2 (MRP2); however, the contribution of SF blood clearance via the bile is still convoluted with other factors, such as renal clearance. In this work, we sought to computationally model SF blood clearance via the bile. First, we converted extant SF fluorescence data from rat whole blood, plasma, and bile to concentrations using calibration curves. Next, based on these SF concentration data, we generated a liver-centric, physiologically-based pharmacokinetic (PBPK) model of SF liver uptake and clearance via the bile. Model simulations show that SF bile concentration is highly sensitive to a change in the activity of hepatic MPR2. These simulations suggest that SF bile clearance along with the PBPK model can be used to quantify the effect of IRI on the activity of MRP2.