Risk assessment of drug–drug interactions using hepatocytes suspended in serum during the drug discovery process
| Autor: | Yasushi Fujioka, Teruaki Okuda, Hideki Hirabayashi, Yohei Kosugi, Toshiya Moriwaki, Tomoko Igari |
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| Rok vydání: | 2013 |
| Předmět: |
Drug
Health Toxicology and Mutagenesis media_common.quotation_subject Pharmacology Biology Toxicology Risk Assessment Biochemistry Inhibitory Concentration 50 Pharmacokinetics Drug Discovery Humans Drug Interactions Enzyme Inhibitors IC50 Cells Cultured media_common Cryopreservation Drug discovery General Medicine Recombinant Proteins Kinetics Blood Area Under Curve Hepatocytes Cytokines Risk assessment Early phase Drug metabolism Human cytochrome |
| Zdroj: | Xenobiotica. 44:336-344 |
| ISSN: | 1366-5928 0049-8254 |
| Popis: | 1. This study optimized the reported approach for the prediction of drug-drug interactions (DDIs) using hepatocytes suspended in serum (HHSS) and provided a practical usage of HHSS in the early and late phases of drug discovery. 2. First, the IC50 was determined using HHSS and evaluated as a qualitative index for DDI risks in the early phase. A retrospective study on clinical DDI cases revealed that inhibitors with IC50 100 μmol/L caused clinical DDIs while those with IC50 100 μmol/L showed weak or no potential for DDIs. Meanwhile, a pragmatic cutoff value could not be determined using previously reported Ki values of recombinant human cytochrome P450s. 3. Second, for a more substantial DDI risk assessment in the later phase, quantitative predictions of clinical DDI based on a static model were attempted by optimizing the most appropriate inhibitor concentration ([I]). The use of hepatic input plasma concentrations as a surrogate for [I] achieved the most successful predictions of the magnitude of increase in the AUC (within a 2-fold range of the observed values for 93.8% of inhibitors). 4. Through this study, we proposed the practical application of HHSS for an effective workflow to explore and profile candidates with less DDI liability. |
| Databáze: | OpenAIRE |
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