Drug-induced cholestasis risk assessment in sandwich-cultured human hepatocytes
| Autor: | Pieter Annaert, Philippe Bachellier, Lysiane Richert, Bruno Heyd, Thomas Zacharias, Audrey Baze, Marlies Oorts |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Drug medicine.medical_specialty media_common.quotation_subject Cmax Pharmacology Fialuridine Toxicology Risk Assessment Bile Acids and Salts 03 medical and health sciences 0302 clinical medicine Diclofenac Cholestasis medicine Humans Urea Cells Cultured media_common Tolcapone business.industry Troglitazone General Medicine medicine.disease Surgery 030104 developmental biology Perhexiline Cyclosporine Hepatocytes Chemical and Drug Induced Liver Injury business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Toxicology in vitro : an international journal published in association with BIBRA. 34 |
| ISSN: | 1879-3177 |
| Popis: | Drug-induced cholestasis (DIC) is recognized as one of the prime mechanisms for DILI. Hence, earlier detection of drug candidates with cholestatic signature is crucial. Recently, we introduced an in vitro model for DIC and evaluated its performance with several cholestatic drugs. We presently expand on the validation of this model by 14 training compounds (TCs) of the EU-EFPIA IMI project MIP-DILI. Several batches of human hepatocytes in sandwich-culture were qualified for DIC assessment by verifying the bile acid-dependent increase in sensitivity to the toxic effects of cyclosporin A. The cholestatic potential of the TCs was expressed by determining the drug-induced cholestasis index (DICI). A safety margin (SM) was calculated as the ratio of the lowest TC concentration with a DICI≤0.80 to the Cmax,total. Nefazodone, bosentan, perhexiline and troglitazone were flagged for cholestasis (SM |
| Databáze: | OpenAIRE |
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