Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Xenobiotica, 2019-01, Vol.49 (1), p.22-35

Ort / Verlag

England: Taylor & Francis

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.