Assessing the Role of Intracellular Binding Protein in Drug-Induced Bile Acid Transporter Inhibition Using Quantitative Systems Pharmacology (QSP) Modeling

Authors: Taneja G, Generaux GT, Howell BA, Woodhead JL
Conference: AAPS
Keywords: bile acid transport, liver injury, protein binding, quantitative systems pharmacology, transporter inhibition
Software: DILIsym®
Division: Quantitative Systems Pharmacology (QSP)

Purpose

Bile acid transporter inhibition has been shown to be an important mechanism of drug-induced liver injury (DILI), but the biophase responsible for the transporter inhibition is unclear. While the free-drug hypothesis would suggest that only unbound drug can inhibit bile acid transporters, there has been success in predicting bile acid transporter inhibitormediated DILI with DILIsym (1,2), which uses total drug concentration to represent the transporter inhibition. The role of intracellular protein binding of bile acids is also unclear.
The goal of the current simulation work was to investigate the impact of drug and bile acid binding kinetics on BSEP inhibition using a mechanistic QSP model.

2018 AAPS Annual Meeting PharmSci 360, November 4-7, 2018, Washington, DC

By Guncha Taneja, Grant Generaux, Brett A. Howell, Jeffrey L. Woodhead