Direct and quantitative evaluation of the major human CYP contribution (fmCYP) to drug clearance using the in vitro Silensomes™ model. (2nd January 2019)

• Record Type: Journal Article
• Authors: Parmentier, Yannick; Pothier, Corinne; Hewitt, Nicola; Vincent, Ludwig; Caradec, Fabrice; Liu, Jia; Lin, Feifei; Trancart, Marie-Michèle; Guillet, Fabrice; Bouaita, Belkacem; Chesne, Christophe; Walther, Bernard
• Is Part Of: Xenobiotica. Volume 49:Number 1(2019:Jan.)
• Page Start: 22
• Page End: 35
• Publication Date: 2019-01-02
• Subjects: Phenotyping -- metabolism -- microsomes -- drug–drug interaction -- cytochrome -- mechanism based inhibitor; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2017.1422156
• Languages: English
• ISSNs: 0049-8254

Abstract

Abstract: 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.