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

作者：Parmentier, Yannick^*; Pothier, Corinne; Hewitt, Nicola; Vincent, Ludwig; Caradec, Fabrice; Liu, Jia; Lin, Feifei; Trancart, Marie-Michele; Guillet, Fabrice; Bouaita, Belkacem; Chesne, Christophe; Walther, Bernard

来源：Xenobiotica, 2019, 49(1): 22-35.

DOI：10.1080/00498254.2017.1422156

• Phenotyping
• metabolism
• microsomes
• drug-drug interaction
• cytochrome
• mechanism based inhibitor

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.

• 出版日期2019-1-2
• 单位中国科学院上海药物研究所