Development of a Quantitative Systems Toxicology Model of Drug-Induced Cholangiocyte Injury in DILIsym

Authors: Taneja G, Siler SQ, Howell BA, Watkins PB, Woodhead JL
Conference: SOT
Keywords: bile acid (BA) homeostasis, Cholangiocyte injury, drug inhibition, drug-induced liver injury, Toxicity
Software: DILIsym®
Division: Quantitative Systems Pharmacology (QSP)

Introduction

  • Cholangiocyte injury accounts for a quarter of drug-induced liver injury (DILI) cases and is associated with higher rates of morbidity and mortality than hepatocellular DILI (Chalasani et al., 2015).
  • There are currently no methods to screen drugs for cholangiocyte toxicity potential at the lead candidate selection phase.
  • Inhibition of multidrug resistance protein 3 (MDR3) by drugs has been shown to correlate with cholangiocyte injury and drug toxicity in humans.
  • MDR3 mediates transport of phospholipids to the bile canaliculus. Inhibition of phospholipid transport reduces micelle formation resulting in free bile acids that can damage cholangiocytes.
  • Clinically, cholangiocyte injury is defined as an isolated rise in serum alkaline phosphatase

By Guncha Taneja, Scott Siler, Brett Howell, Paul Watkins, Jeff Woodhead

Society of Toxicology 58th Annual Meeting and ToxExpo, March 10-14, 2019, Baltimore, MD