Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system
| Autor: | Carlota Oleaga, Anne Riu, Sandra Rothemund, Andrea Lavado, Christopher W. McAleer, Christopher J. Long, Keisha Persaud, Narasimhan Sriram Narasimhan, My Tran, Jeffry Roles, Carlos A. Carmona-Moran, Trevor Sasserath, Daniel H. Elbrecht, Lee Kumanchik, L. Richard Bridges, Candace Martin, Mark T. Schnepper, Gail Ekman, Max Jackson, Ying I. Wang, Reine Note, Jessica Langer, Silvia Teissier, James J. Hickman |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Drug Histamine H1 Antagonists Non-Sedating media_common.quotation_subject Induced Pluripotent Stem Cells Drug Evaluation Preclinical Biophysics Bioengineering 02 engineering and technology Pharmacology Article Cell Line Biomaterials 03 medical and health sciences Pharmacokinetics In vivo Lab-On-A-Chip Devices Humans Medicine Myocytes Cardiac Biomarker Analysis Cyclophosphamide Cells Cultured media_common Cardiotoxicity business.industry In vitro toxicology Equipment Design 021001 nanoscience & nanotechnology Coculture Techniques In vitro 030104 developmental biology Mechanics of Materials Hepatocytes Ceramics and Composites Terfenadine 0210 nano-technology business Immunosuppressive Agents Drug metabolism |
| Zdroj: | Biomaterials. 182:176-190 |
| ISSN: | 0142-9612 |
| DOI: | 10.1016/j.biomaterials.2018.07.062 |
| Popis: | Regulation of cosmetic testing and poor predictivity of preclinical drug studies has spurred efforts to develop new methods for systemic toxicity. Current in vitro assays do not fully represent physiology, often lacking xenobiotic metabolism. Functional human multi-organ systems containing iPSC derived cardiomyocytes and primary hepatocytes were maintained under flow using a low-volume pumpless system in a serum-free medium. The functional readouts for contractile force and electrical conductivity enabled the non-invasive study of cardiac function. The presence of the hepatocytes in the system induced cardiotoxic effects from cyclophosphamide and reduced them for terfenadine due to drug metabolism, as expected from each compound’s pharmacology. A computational fluid dynamics simulation enabled the prediction of terfenadine-fexofenadine pharmacokinetics, which was validated by HPLC-MS. This in vitro platform recapitulates primary aspects of the in vivo crosstalk between heart and liver and enables pharmacological studies, involving both organs in a single in vitro platform. The system enables non-invasive readouts of cardiotoxicity of drugs and their metabolites. Hepatotoxicity can also be evaluated by biomarker analysis and change in metabolic function. Integration of metabolic function in toxicology models can improve adverse effects prediction in preclinical studies and this system could also be used for chronic studies as well. |
| Databáze: | OpenAIRE |
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