Resource Center

Mar 27, 2022
  |  Poster

Simulating Multidrug Resistance Protein 3 (MDR3) Inhibition-Mediated Cholestatic Liver Injury Using DILIsym X, a Quantitative Systems Toxicology (QST) Modeling Platform

Background

  • Inhibition of efflux transporters located on the canalicular membrane of hepatocytes is an important mechanism of cholestatic liver injury, which is clinically characterized by disrupted bile flow and damage to the biliary epithelium (Rodrigues et al., 2014; Kotsampaskou and Ecker, 2017)
  • Drug-induced inhibition of the canalicular phospholipid (PL) floppase MDR3 is often implicated in cholestatic hepatotoxicty
  • Reduction in PL efflux diminishes the ability to form mixed micelles of bile acids (BAs) and PLs in the bile duct, leading to an excess of free biliary BA monomers, which can be toxic at high concentrations (Geuken et al., 2004; Aleo et al., 2017)
  • The epithelial cells of the bile duct, cholangiocytes, respond to this toxic exposure in multiple ways

Methods

  • The human BA and PL sub-models within DILIsym® X (Fig. 1) were updated with new features relevant to cholestatic liver: (1) different modes of MDR3 inhibition, (2) non-MDR3-mediated PL efflux, (3) the cholehepatic shunting of BAs, (4) biliary HCO₃-secretion and its impact on bile flow, BA shunting, and cholangiocyte toxicity, and (5) cholangiocyte regeneration
  • Simulations were performed to evaluate the interplay of these processes in the absence and presence of a hypothetical MDR3 inhibitor (Ki = 1 μM) with one of three modes of inhibition (fig. 2)

Results

Simulations (Fig. 2) showed that:

  • The baseline model recapitulated average literature values for the biliary BA/PL ratio (~10), biliary HCO₃-concentration (~25 mM), bile flow rate (~15 mL/h), and biomarkers including alkaline phosphates (~44 U/L), among other features
  • Non-competitive and mixed (α = 5) inhibition of MDR3 had the most substantial effects on PL efflux and the ensuing cholangiocyte toxicity and adaptation mechanisms, while competitive inhibition had a minor impact
  • When MDR3 was inhibited noncompetitively, the model predicted ~doubling of both the biliary BA/PL ratio and HCO₃-concentration, and recapitulated the ability of HCO₃-elevations to increase bile flow, and decrease BA shunting and cholangiocyte toxicity

Conclusions

  • The refined BA and PL sub-models within DILIsym X represent various processes crucial to bile duct health and cholestatic liver injury, and show promise to be used for predictions of MDR3 inhibition-mediated cholestatic liver injury in humans

Acknowledgements

  • This research was supported by the members of the DILI-sim Initiative, a public-private partnership involving scientists from academia, the FDA, and industry

By: James J. Beaudoin, Jeffry Adiwidjaja, Kyunghee Yang, Jeffrey L. Woodhead

Presented at Society of Toxicology (SOT) 61st Annual Meeting and ToxExpo, March 27-31, 2022

Contact Us About This Poster