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Silensomes™

Silensomes™ are irreversibly inactivated pooled human liver microsomes (HLM) in which cytochromes P450 (CYP) enzymes have been chemically knocked down using mechanism-based inhibitors (MBI). Silensomes™ is available as a ready-to-use product, where CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 can be individually chemically knocked-down. The technology guarantees over 80% inhibition of the targeted CYP and less than 20% off-target impact on the other CYPs.

Drug-drug interaction can significantly impact drug safety and efficacy. Prediction of the risk of drug-drug interaction is part of the development of a new drug candidate and the registration dossier. In vitro identification and measurement of the contribution of the major CYPs involved in the human metabolism of a new drug candidate, also called “CYP phenotyping”, helps predicting the impact of a co-administered drug (perpetrator) on the pharmacokinetics of a new chemical entity (victim).

Currently, for CYP phenotyping, a battery of in vitro tests (antibody or chemical inhibition, estimation of fraction metabolized by recombinant human enzymes, and correlation analysis) recommended by the regulatory agencies (EMA/FDA) is required. The major drawbacks of the battery are lack of quantitative measurement of the contribution of each CYP in the metabolism of a drug (correlation analysis), lack of specific commercially available anti-CYP antibodies and last but not least human recombinant CYPs do not fully represent the in vivo liver enzymes.

To overcome the listed limitations, the Silensomes™ product was developed (patent owner Servier Laboratories, world-wide licensee Biopredic).

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Silensomes™ is the model of choice for determination of the CYP contribution all along the development plan of a new chemical entity. It is a unique solution for a direct quantitation of the fraction metabolized (fm (f for fraction, m for metabolized)) by different hepatic CYP enzymes. Main advantages of the product are:

  • Irreversible inhibition of CYPs, using mechanism-based inhibitors
  • Possibility for parallel incubation with control HLMs
  • Quantitative data: the true contribution of the 9 main CYP450s in the metabolism of the compound
  • Better representation of in vivo situation by using human liver microsomes in comparison to the use of recombinant enzymes
  • One single model and protocol for CYP phenotyping assays, instead of a battery of in vitro tests. The 9 main CYPs involved in the drug metabolism are included in the Silensomes™ line of products

Silensomes™ are relevant for both compound screening and for regulatory filing.

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Good correlation between the in vivo Fm and the calculated in vitro Fm using Silensomes™. The analysis was done on 10 multi-CYP substrates and showed that for all tested compounds, the in vitro CYP contributions (fm) obtained with Silensomes™ correlate very well with the in vivo values.

A simple and at the same time content-rich assay

  • In one assay you can:
    • Obtain the Intrinsic clearance of your compound
    • Determine which CYPs are involved in the biotransformation
    • Quantify the CYPs involved.

VISIT OUR SHOP

Order Silensomes™from Biopredic International

References

Parmentier et al. (2018) Xenobiotica, doi: 10.1080/00498254.2017.1422156

SaferWorldbyDesign

SaferWorldbyDesign integrates in silico and in vitro methods to develop standard and premium Integrated Approaches to Testing and Assessment (IATAs), including methods that support ingredient and formulation screening and testing, product design and the preparation of Regulatory Dossiers.

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Edelweiss Connect GmbH is registered as a limited company with Handelsregisteramt of Kanton Basel-Stadt

Swiss ID (UID) number: CHE-114.414.615

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