Mechanistic Modeling Reveals the Most Important Unknowns in Bile Acid-Mediated DILI

Authors: Woodhead JL, Yang K, Brouwer KL, Watkins PB, Siler SQ, Howell BA
Conference: SOT
Keywords: DILI, drug-induced liver injury, transporter inhibitor
Software: DILIsym®
Division: Quantitative Systems Pharmacology (QSP)

Abstract

BSEP inhibition and consequent bile acid (BA) buildup has been proposed to be an important mechanism in druginduced liver injury (DILI). There are many gaps in the knowledge of BA homeostasis and its disruption by transporter inhibitors. Modeling can help us understand which of these knowledge gaps should be filled first in order to provide maximum understanding. We have constructed a model of BA homeostasis and toxicity within DILIsym™ , a mechanistic model of DILI that includes bile acid flux into and out of hepatocytes, the role of the farnesoid X receptor (FXR) in the regulation of BA transport and synthesis, and gallbladder BA release and recirculation. We first analyzed our system’s behavior in the presence of a simulated BSEP inhibitor. We predict a 134% increase in total periportal hepatocyte content of amide conjugated chenodeoxycholic acid (CDCA) and a 311% increase in sulfate-conjugated lithocholic acid (LCA). However, the simulated BSEP inhibition resulted in a decrease in unconjugated CDCA, amide-conjugated LCA, and unconjugated LCA. Significant zonal effects were also witnessed; accumulation was 6x greater as a percentage of baseline in centrilobular hepatocytes, though centrilobular concentrations remained lower than periportal concentrations. We next performed a sensitivity analysis on our system’s response to BSEP inhibition in order to determine which parameter has the greatest effect on hepatocyte content of BAs and hence BSEP inhibitor-induced hepatotoxicity. We found that the most important unknowns in the system are the level of BSEP expression in the cell and the magnitude of the FXRmediated regulatory signal, while other parameters such as the affinity constants for basolateral CDCA and LCA transport were less important. We conclude that the highest priorities for wet lab research to inform our model and enhance our understanding of BSEP inhibitor mediated DILI are: 1) quantifying the relationship among intrahepatocyte concentrations of individual bile acids, FXR activation, and transporter activity; and 2) quantifying the toxicity caused by CDCA amide conjugates and LCA sulfate conjugates.

SOT 52nd Annual Meeting and ToxExpo, March 10-14, 2013, San Antonio, Texas

By Jeffrey L. Woodhead, Kyunghee Yang, Kim L. Brouwer, Paul B. Watkins, Scott Q. Siler, Brett A. Howell