Journal: Clinical pharmacology and therapeutics

Article Title: Systems Pharmacology Modeling Predicts Delayed Presentation and Species Differences in Bile Acid-Mediated Troglitazone Hepatotoxicity

doi: 10.1038/clpt.2014.158

Figure Lengend Snippet: Hepatic and systemic disposition of drugs/metabolites are simulated using a physiologically-based pharmacokinetic (PBPK) model ( Drug PBPK Model ). The Bile Acid Homeostasis Model represents hepatobiliary disposition and enterohepatic recirculation of lithocholic acid (LCA) and chenodeoxycholic acid (CDCA) species, and all other (bulk) bile acids. Using bile acid transport inhibition constants of drugs/metabolites (e.g., K i , IC 50 ), altered bile acid disposition is simulated. Increased hepatocellular accumulation of bile acids inhibits hepatic ATP synthesis and decreases intracellular ATP concentrations ( Cellular ATP Model ), leading to necrotic cell death ( Hepatocyte Life Cycle Model ) and elevations in serum biomarkers of hepatocellular injury and function (e.g., ALT, AST, bilirubin) ( Biomarker Model ). Loss of hepatocytes will subsequently influence drug and bile acid disposition (dashed lines), allowing dynamic interaction between kinetics and toxicity mechanisms. Details regarding the construction and structures of sub-models can be found in the .

Article Snippet: In DILIsym, CDCA, LCA, and their conjugates were exclusively modeled as the toxic BAs.

Techniques: Inhibition, Biomarker Discovery

Journal: Clinical pharmacology and therapeutics

Article Title: Systems Pharmacology Modeling Predicts Delayed Presentation and Species Differences in Bile Acid-Mediated Troglitazone Hepatotoxicity

doi: 10.1038/clpt.2014.158

Figure Lengend Snippet: Predicted maximum hepatic accumulation of CDCA and LCA species and DILI responses (i.e., minimum hepatic ATP, minimum viable liver mass, maximum serum ALT) post-dose in human SimPops at oral doses of 200 (green triangle), 400 (blue circle), or 600 (red diamond) mg/day TGZ for 6months (A), and rat SimPops at oral doses of 5 (blue circle) or 25 (red diamond) mg/kg/day for 6months (B).

Article Snippet: In DILIsym, CDCA, LCA, and their conjugates were exclusively modeled as the toxic BAs.

Techniques:

Journal: Clinical pharmacology and therapeutics

Article Title: Systems Pharmacology Modeling Predicts Delayed Presentation and Species Differences in Bile Acid-Mediated Troglitazone Hepatotoxicity

doi: 10.1038/clpt.2014.158

Figure Lengend Snippet: List of parameters varied in the human and rat SimPops and results of multiple regression analysis in human SimPops administered 600 mg/day troglitazone (TGZ) for 6 months Human and rat population samples incorporating variability in parameters governing bile acid homeostasis (Bile Acid SimPops) have been constructed previously. 20 Four parameters in the Drug PBPK Sub-model and two system-specific parameters also were varied. (See supplementary material for methods and data used for construction of SimPops). In the human SimPops administered 600 mg/day TGZ for 6 months, a multiple regression analysis was performed to identify the most important parameters in TGZ-mediated hepatotoxicity using 16 varied parameters as independent variables and minimum hepatic ATP as the dependent variable. Statistical significance and standardized coefficients were calculated using JMP 10.

Article Snippet: In DILIsym, CDCA, LCA, and their conjugates were exclusively modeled as the toxic BAs.

Techniques: Construct, Inhibition