title: Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI.
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.
authors.affiliation: The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Woodhead
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: K
authors.initials: K
authors.lastname: Yang
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: K L R
authors.initials: KL
authors.lastname: Brouwer
authors.affiliation: The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Siler
authors.affiliation: DMPK, Drug Safety and Metabolism, AstraZeneca R&D Alderley Park, Macclesfield, UK.
authors.forename: S H
authors.initials: SH
authors.lastname: Stahl
authors.affiliation: Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Ambroso
authors.affiliation: Investigative Preclinical Toxicology, Safety Assessment, GlaxoSmithKline R&D, Ware, UK.
authors.forename: D
authors.initials: D
authors.lastname: Baker
authors.affiliation: The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Watkins
authors.affiliation: The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Howell