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Xenobiotica. 2018 Jan 10:1-14. doi: 10.1080/00498254.2017.1422156. [Epub ahead of print]

Direct and quantitative evaluation of the major human CYP contribution (fmCYP) to drug clearance using the in vitro Silensomes™ model.

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a Department of Biopharmaceutical Research , Technologie Servier , Orléans Cedex , France.
b Scientific Writing Services , Erzhausen , Germany.
c SIMM-SERVIER Joint Biopharmacy Laboratory, Shanghai Institute of Materia Medica , Shanghai , China.
d Eurosafe , Saint-Grégoire , France , and.
e Biopredic International , Rennes , France.


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 fmCYP2B6 measured using CYP2B6-Silensomes to adjust the fmCYP2D6. 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.


Phenotyping; cytochrome; drug–drug interaction; mechanism based inhibitor; metabolism; microsomes

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