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

Xenobiotica. 2019 Jan;49(1):22-35. doi: 10.1080/00498254.2017.1422156. Epub 2018 Jan 10.


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.

Keywords: Phenotyping; cytochrome; drug–drug interaction; mechanism based inhibitor; metabolism; microsomes.

MeSH terms

  • Cytochrome P-450 Enzyme System / metabolism*
  • Humans
  • In Vitro Techniques
  • Inactivation, Metabolic
  • Metabolic Clearance Rate
  • Microsomes, Liver / metabolism*
  • Models, Biological*


  • Cytochrome P-450 Enzyme System