Long-enduring primary hepatocyte-based co-cultures improve prediction of hepatotoxicity
| Autor: | Eitan Pludwinski, Cheul H. Cho, James S. MacDonald, Amit Parekh, Jacquelyn Dwyer, Zaid Jayyosi, Robert Freedman, Eric Novik, Anil B. Shrirao, James K. Morelli |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Drug Time Factors Cell Survival media_common.quotation_subject Primary Cell Culture Cell Communication Pharmacology Toxicology Risk Assessment 030226 pharmacology & pharmacy Cell Line Rats Sprague-Dawley 03 medical and health sciences Dogs 0302 clinical medicine Species Specificity In vivo Animals Humans Medicine Dosing Viability assay Cytotoxicity media_common Liver injury Dose-Response Relationship Drug business.industry Cell Differentiation Fibroblasts medicine.disease Coculture Techniques 030104 developmental biology medicine.anatomical_structure Hepatocyte Hepatocytes Animal studies Chemical and Drug Induced Liver Injury business |
| Zdroj: | Toxicology and Applied Pharmacology. 336:20-30 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2017.09.013 |
| Popis: | The failure of drug candidates during clinical trials and post-marketing withdrawal due to Drug Induced Liver Injury (DILI), results in significant late-stage attrition in the pharmaceutical industry. Animal studies have proven insufficient to definitively predict DILI in the clinic, therefore a variety of in vitro models are being tested in an effort to improve prediction of human hepatotoxicity. The model system described here consists of cryopreserved primary rat, dog or human hepatocytes co-cultured together with a fibroblast cell line, which aids in the hepatocytes' maintenance of more in vivo -like characteristics compared to traditional hepatic mono-cultures, including long term viability and retention of activity of cytochrome P450 isozymes. Cell viability was assessed by measurement of ATP following treatment with 29 compounds having known hepatotoxic liabilities. Hμrelrat™, Hμreldog™, and Hμrelhuman™ hepatic co-cultures were treated for 24 h, or under repeat-dosing for 7 or 13 days, and compared to rat and human hepatic mono-cultures following single-dose exposure for 24 h. The results allowed for a comparison of cytotoxicity, species-specific responses and the effect of repeat compound exposure on the prediction of hepatotoxic potential in each model. Results show that the co-culture model had greater sensitivity compared to that of the hepatic mono-cultures. In addition, “time-based ratios” were determined by dividing the compounds' 24-hour TC 50 /C max values by TC 50 /C max values measured after dosing for either 7 or 13 days. The results suggest that this approach may serve as a useful adjunct to traditional measurements of hepatotoxicity, improving the predictive value of early screening studies. |
| Databáze: | OpenAIRE |
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