| Autor: |
Parmentier Y; a Department of Biopharmaceutical Research , Technologie Servier , Orléans Cedex , France., Pothier C; a Department of Biopharmaceutical Research , Technologie Servier , Orléans Cedex , France., Hewitt N; b Scientific Writing Services , Erzhausen , Germany., Vincent L; a Department of Biopharmaceutical Research , Technologie Servier , Orléans Cedex , France., Caradec F; a Department of Biopharmaceutical Research , Technologie Servier , Orléans Cedex , France., Liu J; c SIMM-SERVIER Joint Biopharmacy Laboratory, Shanghai Institute of Materia Medica , Shanghai , China., Lin F; c SIMM-SERVIER Joint Biopharmacy Laboratory, Shanghai Institute of Materia Medica , Shanghai , China., Trancart MM; d Eurosafe , Saint-Grégoire , France , and., Guillet F; d Eurosafe , Saint-Grégoire , France , and., Bouaita B; e Biopredic International , Rennes , France., Chesne C; e Biopredic International , Rennes , France., Walther B; a Department of Biopharmaceutical Research , Technologie Servier , Orléans Cedex , France. |
| Abstrakt: |
1. We have applied the concept of using MBIs to produce CYP-Silensomes to quantify the contribution of the major CYPs to drug metabolism (fmCYP). 2. The target CYPs were extensively and selectivity inhibited by the selected MBIs, while non-target CYPs were inhibited by less than 20% of the homologous control activities. Only CYP2D6-Silensomes exhibited a CYP2B6 inhibition that could be easily and efficiently encountered by subtracting the fm CYP2B6 measured using CYP2B6-Silensomes to adjust the fm CYP2D6 . 3. To validate the use of a panel of 6 CYP-Silensomes, we showed that the fmCYP values of mono- and multi-CYP metabolised drugs were well predicted, with 70% within ± 15% accuracy. Moreover, the correlation with observed fmCYP values was higher than that for rhCYPs, which were run in parallel using the same drugs (<45% within ±15% accuracy). Moreover, the choice of the RAF substrate in rhCYP predictions was shown to affect the accuracy of the fmCYP measurement. 4. These results support the use of CYP1A2-, CYP2B6-, CYP2C8-, CYP2C9-, CYP2D6 and CYP3A4-Silensomes to accurately predict fmCYP values during the in vitro enzyme phenotyping assays in early, as well as in development, phases of drug development. |
