Related Experiment Video
Updated: Apr 27, 2026

Author Spotlight: Developing a Simple and Robust Hepatic Model for Pharmacological and Toxicological Applications
Published on: October 20, 2023
Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI
J L Woodhead1, K Yang2, K L R Brouwer2
1The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA.
Abstract:
Bile salt export pump (BSEP) inhibition has been proposed to be an important mechanism for drug-induced liver injury (DILI). Modeling can prioritize knowledge gaps concerning bile acid (BA) homeostasis and thus help guide experimentation. A submodel of BA homeostasis in rats and humans was constructed within DILIsym, a mechanistic model of DILI. In vivo experiments in rats with glibenclamide were conducted, and data from these experiments were used to validate the model. The behavior of DILIsym was analyzed in the presence of a simulated theoretical BSEP inhibitor. BSEP inhibition in humans is predicted to increase liver concentrations of conjugated chenodeoxycholic acid (CDCA) and sulfate-conjugated lithocholic acid (LCA) while the concentration of other liver BAs remains constant or decreases. On the basis of a sensitivity analysis, the most important unknowns are the level of BSEP expression, the amount of intestinal synthesis of LCA, and the magnitude of farnesoid-X nuclear receptor (FXR)-mediated regulation.
Related Concept Videos
Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
A recent model describes pravastatin's hepatobiliary excretion,...
Mechanistic Models: Overview of Compartment Models
Effect of Hepatic Disease on Pharmacokinetics: Pathophysiologic Assessment and Liver Function Test
Effect of Hepatic Disease on Pharmacokinetics: Drug Dosing and Hepatic Blood Flow
Hepatic Drug Excretion: Influencing Factors
Hepatic Drug Excretion: Enterohepatic Cycling
Post-release drugs and metabolites can be reabsorbed into the body from the intestine. For conjugated metabolites like glucuronides, reabsorption requires enzymatic hydrolysis by intestinal microflora. This...

