ArticleClinical pharmacology and therapeutics2014
Systems pharmacology modeling predicts delayed presentation and species differences in bile acid-mediated troglitazone hepatotoxicity.
Article in Clinical pharmacology and therapeutics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
42 citing papers in PubMed, 95 citations in OpenAlex.
- Quantitative systems toxicology (QST) reproduces species differences in PF-04895162 liver safety due to combined mitochondrial and bile acid toxicity.Pharmacology research & perspectives · 2019Trial
- Using Quantitative Systems Toxicology to Investigate Observed Species Differences in CKA-Mediated Hepatotoxicity.Toxicological sciences : an official journal of the Society of Toxicology · 2018Trial
- [Effect of the combination of alkaloids from Euodiae Fructus and berberine in Zuojin Pill on cytotoxicity in HepG2 cells].Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences · 2025Article
- Drug metabolizing enzymes and transporters, and their roles for the development of drug-induced liver injury.Expert opinion on drug metabolism & toxicology · 2025Review
- Advancing hepatotoxicity assessment: current advances and future directions.Toxicological research · 2025Review
- Review
- Multi-tissue metabolomics analysis reveals susceptible factors for chemotherapy-induced hepatotoxicity in colorectal cancer patients.Frontiers in pharmacology · 2025Article
- Advances in drug-induced liver injury research: in vitro models, mechanisms, omics and gene modulation techniques.Cell & bioscience · 2024Review
- Membrane transporters in drug development and as determinants of precision medicine.Nature reviews. Drug discovery · 2024Review
- Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.Pharmacological research · 2024Article
- Hepatic Bile Acid Transporters and Drug-induced Hepatotoxicity.Toxicologic pathology · 2023Review
- A decade of liver organoids: Advances in disease modeling.Clinical and molecular hepatology · 2023Review
- Review
- Role and Regulation of Hepatobiliary ATP-Binding Cassette Transporters during Chemical-Induced Liver Injury.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
- Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition.Frontiers in pharmacology · 2022Article
- [Cytotoxicity and underlying mechanism of evodiamine in HepG2 cells].Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences · 2021Article
- Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction.Acta pharmaceutica Sinica. B · 2021Review
- Human-relevant mechanisms and risk factors for TAK-875-Induced liver injury identified via a gene pathway-based approach in Collaborative Cross mice.Toxicology · 2021Article
- High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell-Derived Organoids.Gastroenterology · 2021Article
- Drug Dosing Recommendations for All Patients: A Roadmap for Change.Clinical pharmacology and therapeutics · 2021Review
Corrections and comments
- Commented on by
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Troglitazone (TGZ) causes delayed, life-threatening drug-induced liver injury in some patients but was not hepatotoxic in rats. This study investigated altered bile acid homeostasis as a mechanism of TGZ hepatotoxicity using a systems pharmacology model incorporating drug/metabolite disposition, bile acid physiology/pathophysiology, hepatocyte life cycle, and liver injury biomarkers. In the simulated human population, TGZ (200-600 mg/day × 6 months) resulted in delayed increases in serum alanine transaminase >3× the upper limit of normal in 0.3-5.1%, with concomitant bilirubin elevations >2× the upper limit of normal in 0.3-3.6%, of the population. By contrast, pioglitazone (15-45 mg/day × 6 months) did not elicit hepatotoxicity, consistent with clinical data. TGZ was not hepatotoxic in the simulated rat population. In summary, mechanistic modeling based only on bile acid effects accurately predicted the incidence, delayed presentation, and species differences in TGZ hepatotoxicity, in addition to predicting the relative liver safety of pioglitazone. Systems pharmacology models integrating physiology and experimental data can evaluate drug-induced liver injury mechanisms and may be useful to predict the hepatotoxic potential of drug candidates.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.