Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System
| العنوان: | Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System |
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| المؤلفون: | CL Stokes, David J. Hughes, Tomasz Kostrzewski, Linda G. Griffith, Nikolaos Tsamandouras, Murat Cirit |
| المساهمون: | Massachusetts Institute of Technology. Biotechnology Process Engineering Center, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Mechanical Engineering, Tsamandouras, Nikolaos, Griffith, Linda G, Cirit, Murat |
| المصدر: | ASPET The Journal of Pharmacology and Experimental Therapeutics |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Metabolite, Population, Context (language use), Pharmacology, Biology, 030226 pharmacology & pharmacy, Metabolism, Transport, and Pharmacogenomics, Tissue Culture Techniques, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Pharmacokinetics, In vivo, Lactate dehydrogenase, medicine, Humans, Tissue Distribution, education, Serum Albumin, Cryopreservation, education.field_of_study, L-Lactate Dehydrogenase, 3. Good health, Perfusion, Phenotype, 030104 developmental biology, Liver, Pharmaceutical Preparations, chemistry, Phenacetin, Hepatocytes, Molecular Medicine, Drug metabolism, medicine.drug |
| الوصف: | 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. United States. Defense Advanced Research Projects Agency. Microphysiological Systems Program (Grant W911NF-12-2-0039) National Institutes of Health (U.S.). Microphysiological Systems Program (Grant 4-UH3-TR000496-03) |
| وصف الملف: | application/pdf |
| تدمد: | 1521-0103 0022-3565 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::474674616912e33a2d0868a3c0652a04Test https://doi.org/10.1124/jpet.116.237495Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....474674616912e33a2d0868a3c0652a04 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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