ArticleClinical pharmacology and therapeutics2017
Systems pharmacology modeling of drug-induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters.
Article in Clinical pharmacology and therapeutics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
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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
21 citing papers in PubMed, 37 citations in OpenAlex.
- Using Quantitative Systems Toxicology to Investigate Observed Species Differences in CKA-Mediated Hepatotoxicity.Toxicological sciences : an official journal of the Society of Toxicology · 2018Trial
- Acute and 28-Day Toxicity Evaluation of New Pleuromutilin Derivative 4g.Journal of applied toxicology : JAT · 2026Article
- Risk Assessment for Drug-Induced Hyperbilirubinemia: A Mechanistic Approach.CPT: pharmacometrics & systems pharmacology · 2026Article
- Development of a Physiologically Based Model of Bilirubin Metabolism in Health and Disease and Its Comparison With Real-World Data.CPT: pharmacometrics & systems pharmacology · 2026Article
- Inhibition of OATP1B1/3 Rather Than UGT1A1 May Be the Major Cause of the Bilirubin Elevation After Atazanavir Administration.Clinical pharmacology and therapeutics · 2025Article
- Drug metabolizing enzymes and transporters, and their roles for the development of drug-induced liver injury.Expert opinion on drug metabolism & toxicology · 2025Review
- Review
- A Comparison of Postmortem Serum and Pericardial Fluid Total Bilirubin Levels With Antemortem Data.Cureus · 2025Article
- ABCC2 p.R393W variant contributes to Dubin-Johnson syndrome by targeting MRP2 to proteasome degradation.eGastroenterology · 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
- Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review.Clinical pharmacokinetics · 2022Review
- The association of transporter ABCC2 (MRP2) genetic variation and drug-induced hyperbilirubinemia.Journal of the Chinese Medical Association : JCMA · 2021Article
- 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
- The DILI-sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation.Clinical and translational science · 2019Review
- 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
- PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3.CPT: pharmacometrics & systems pharmacology · 2018Article
- Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches.Clinical pharmacology and therapeutics · 2018Article
- Gaining Mechanistic Insight Into Coproporphyrin I as Endogenous Biomarker for OATP1B-Mediated Drug-Drug Interactions Using Population Pharmacokinetic Modeling and Simulation.Clinical pharmacology and therapeutics · 2018Article
- Improving Interpretation of New and Old Serum Biomarkers of Drug-Induced Liver Injury Through Mechanistic Modeling.CPT: pharmacometrics & systems pharmacology · 2018Article
- In silico modeling to optimize interpretation of liver safety biomarkers in clinical trials.Experimental biology and medicine (Maywood, N.J.) · 2018Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model-predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir-mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug-induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin.
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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.