ArticleThe Journal of pharmacology and experimental therapeutics2017
Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System.
Article in The Journal of pharmacology and experimental therapeutics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers, 2 of them syntheses that pooled it.
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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
62 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Integration of microphysiological systems with computational and digital twin modeling for pharmaceutical development: a systematic review.Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques · 2026Pooled it
- Engineered tissues and strategies to overcome challenges in drug development.Advanced drug delivery reviews · 2020Pooled it
- Assessing drug-induced liver injury liabilities in human and animal hepatocytes under static and perfused spheroid culture conditions.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- Organ-on-chip bridging musculoskeletal disease modeling and precision therapeutic discovery.Trends in biotechnology · 2026Review
- Article
- A vascularized liver microphysiological system captures key features of hepatic insulin resistance and monocyte infiltration.Nature communications · 2026Article
- A microphysiological model of human MASLD reveals paradoxical response to resmetirom.Communications biology · 2026Article
- Review
- Microengineered patient-derived endometrium-on-a-chip for the evaluation of endometrial receptivity and personalised translational medicine.Nature communications · 2025Article
- Digital twin-enhanced three-organ microphysiological system for studying drug pharmacokinetics in pregnant women.Frontiers in pharmacology · 2025Article
- Article
- A virtual scalable model of the Hepatic Lobule for acetaminophen hepatotoxicity prediction.NPJ digital medicine · 2024Article
- Microphysiological systems to advance human pathophysiology and translational medicine.Journal of applied physiology (Bethesda, Md. : 1985) · 2024Review
- Bridging systems biology and tissue engineering: Unleashing the full potential of complex 3DBiophysics reviews · 2024Review
- Modeling Tumor Cell Dormancy in an Ex Vivo Liver Metastatic Niche.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Modeling Liver Development and Disease in a Dish.International journal of molecular sciences · 2023Review
- A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications.The AAPS journal · 2023Article
- Reproducibility and Robustness of a Liver Microphysiological System PhysioMimix LC12 under Varying Culture Conditions and Cell Type Combinations.Bioengineering (Basel, Switzerland) · 2023Article
- Design, Simulation, and Evaluation of Polymer-Based Microfluidic Devices via Computational Fluid Dynamics and Cell Culture "On-Chip".Biosensors · 2023Article
- Microfluidic Liver-on-a-Chip for Preclinical Drug Discovery.Pharmaceutics · 2023Review
2 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors.
Funding
Abstract
In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from five different donors cultured in a perfused three-dimensional human liver microphysiological system, and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of six compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol, and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability [lactate dehydrogenase (LDH) release, albumin, and urea production]. Drug depletion data were analyzed with mixed-effects modeling. Substantial interdonor variability was observed with respect to gene expression levels, drug metabolism, and other measured hepatocyte functions. Specifically, interdonor variability in intrinsic metabolic clearance ranged from 24.1% for phenacetin to 66.8% for propranolol (expressed as coefficient of variation). Albumin, urea, LDH, and cytochrome P450 mRNA levels were identified as significant predictors of in vitro metabolic clearance. Predicted clearance values from the liver microphysiological system were correlated with the observed in vivo values. A population physiologically based pharmacokinetic model was developed for lidocaine to illustrate the translation of the in vitro output to the observed pharmacokinetic variability in vivo. Stochastic simulations with this model successfully predicted the observed clinical concentration-time profiles and the associated population variability. This is the first study of population variability in drug metabolism in the context of a microphysiological system and has important implications for the use of these systems during the drug development process.
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