ArticleFrontiers in pharmacology2014
Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury.
Article in Frontiers in pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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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.
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Who cites it
38 citing papers in PubMed, 92 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
- Translational Toxicology ofInternational journal of molecular sciences · 2026Article
- Insights into the Biochemical and Immune Mechanisms in Drug-Induced Liver Injury Pathogenesis.Chemical research in toxicology · 2026Review
- Ginger and Its Purified Major Components Inhibit Clinically Relevant Uptake and Efflux Transporters In Vitro.Pharmaceutics · 2026Article
- Review
- Novel Cyclohexyl Amido Acid Antagonists of Lysophosphatidic Acid Type 1 Receptor for the Treatment of Pulmonary Fibrosis.ACS medicinal chemistry letters · 2025Article
- Advances in drug-induced liver injury research: in vitro models, mechanisms, omics and gene modulation techniques.Cell & bioscience · 2024Review
- High-Throughput Assessment of Bile Salt Export Pump Inhibition Using RapidFire-MS and DESI-MS.ACS medicinal chemistry letters · 2024Article
- An In Silico Platform to Predict Cardiotoxicity Risk of Anti-tumor Drug Combination with hiPSC-CMs Based In Vitro Study.Pharmaceutical research · 2024Article
- The Combination of a Human Biomimetic Liver Microphysiology System with BIOLOGXsym, a Quantitative Systems Toxicology (QST) Modeling Platform for Macromolecules, Provides Mechanistic Understanding of Tocilizumab- and GGF2-Induced Liver Injury.International journal of molecular sciences · 2023Article
- Comparing the Liver Safety Profiles of 4 Next-Generation CGRP Receptor Antagonists to the Hepatotoxic CGRP Inhibitor Telcagepant Using Quantitative Systems Toxicology Modeling.Toxicological sciences : an official journal of the Society of Toxicology · 2022Article
- Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition.Frontiers in pharmacology · 2022Article
- Deciphering the Underlying Mechanisms of Formula Le-Cao-Shi Against Liver Injuries by Integrating Network Pharmacology, Metabonomics, and Experimental Validation.Frontiers in pharmacology · 2022Article
- Assessing Effects of BHV-0223 40 mg Zydis Sublingual Formulation and Riluzole 50 mg Oral Tablet on Liver Function Test Parameters Utilizing DILIsym.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling.Pharmaceutical research · 2020Article
- Blood-Bile Barrier: Morphology, Regulation, and Pathophysiology.Gene expression · 2019Review
- The DILI-sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation.Clinical and translational science · 2019Review
- Analyzing the Mechanisms Behind Macrolide Antibiotic-Induced Liver Injury Using Quantitative Systems Toxicology Modeling.Pharmaceutical research · 2019Article
- Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation and Mitochondrial Dysfunction in TAK-875-Induced Liver Injury.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Inhibition of the bile salt export pump (BSEP) has been linked to incidence of drug-induced liver injury (DILI), presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels. We also simulate bosentan in rats in order to illuminate potential reasons behind the lack of toxicity in rats compared to the toxicity observed in humans. DILIsym® predicts that bosentan, but not telmisartan, will cause mild hepatocellular ATP decline and serum ALT elevation in a simulated population of humans. The difference in hepatotoxic potential between bosentan and telmisartan is consistent with clinical observations. However, DILIsym® underpredicts the incidence of bosentan toxicity. DILIsym® also predicts that bosentan will not cause toxicity in a simulated population of rats, and that the difference between the response to bosentan in rats and in humans is primarily due to the less toxic bile acid pool in rats. Our simulations also suggest a potential synergistic role for bile acid accumulation and mitochondrial electron transport chain (ETC) inhibition in producing the observed toxicity in CP-724,714, and suggest that CP-724,714 metabolites may also play a role in the observed toxicity. Our work also compares the impact of competitive and noncompetitive BSEP inhibition for CP-724,714 and demonstrates that noncompetitive inhibition leads to much greater bile acid accumulation and potential toxicity. Our research demonstrates the potential for mechanistic modeling to contribute to the understanding of how bile acid transport inhibitors cause DILI.
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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.