  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.
