Reactive Metabolite Screening Service

At Creative Biolabs, our team of experts utilizes state-of-the-art technology and methods to screen for reactive metabolites. By screening for reactive metabolites, we aim to assess the potential safety risks associated with a drug candidate. Our assays provide valuable insights into the metabolic fate of drugs and identify any potential toxicities that may arise during their use.

Why Reactive Metabolite Assay?

Reactive metabolite screening is a crucial aspect of drug development and toxicology research. It involves the identification and assessment of potentially toxic metabolites, which are produced when drugs or other xenobiotics are metabolized by the body. Reactive metabolites are capable of reacting with biological macromolecules, such as DNA, RNA, or proteins, leading to potential toxicities or mutagenic effects, including DNA damage, protein modification, and lipid peroxidation. Therefore, it is essential to identify and evaluate these metabolites to avoid potential safety concerns in later stages of development.

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Fig.1 The toxicities of reactive metabolites. ¹

What We Can Offer

A reactive metabolite screening assay involves incubating the drug with liver microsomes or hepatocytes and then measuring the formation of reactive metabolites using various analytical techniques. We offer a range of assays, including glutathione trapping assay, cysteine trapping assay, cyanide trapping assay, and stable isotope labeling approaches, to comprehensively evaluate the potential for reactive metabolite formation. These assays allow us to detect and quantify reactive metabolites formed during the incubation of drugs with liver microsomes or hepatocytes.

There are several methods we offer to screen for reactive metabolites:

Glutathione Trapping Assay

Glutathione (GSH) is a common target for reactive metabolites, as it can form adducts with electrophilic intermediates. We offer the GSH trapping service that typically involves incubating the test compound with liver microsomes or hepatocytes in the presence of GSH, which acts as a trapping agent for reactive metabolites. The metabolite-GSH conjugates formed are then analyzed using analytical techniques such as liquid chromatography-mass spectrometry (LC-MS) to identify the reactive metabolites and assess their potential risks.

In addition, we offer cysteine (Cys) trapping and cyanide (KCN) service as an alternative study of GSH trapping.

Covalent Binding Assay

Covalent binding assays are considered the most accurate tool in drug development due to their ability to predict the potential toxicity of a drug candidate. These assays are typically performed using radiolabeled compounds, such as ³H or ¹⁴C. However, it is rare to conduct it in early-stage development because of the long and costly processes.

Cytotoxicity Assay

Reactive metabolites can lead to cellular damage and cytotoxicity. By exposing cells to the test compound and measuring cell viability or other markers of cell damage, such as ATP levels or LDH release, reactive metabolites can be identified.

Workflow of Our Reactive Metabolite Screening Service

Highlights

High-Throughput, Quantitative Screening

Utilize our efficient ³⁵S-Cysteine assay, which enables the rapid screening and quantitative ranking of up to 30 lead compounds per plate, maximizing the throughput of your Sar-to-Safety campaigns.

Comprehensive Metabolic Coverage

Our assays ensure maximum coverage by incorporating cofactors for both NADPH and UDPGA metabolism, mitigating the risk of overlooking toxic metabolites formed by conjugation pathways like glucuronidation.

Gold-Standard Structural Confirmation

We employ state-of-the-art LC-HRMS and stable isotope labeling to generate the signature isotopic doublet, providing definitive proof and mass accuracy for the structural identity of the reactive adduct.

Actionable Risk Mitigation Reports

Creative Biolabs provides more than raw data; our final reports include expert, science-backed recommendations for structural de-risking to guide your medicinal chemistry efforts immediately.

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Customer Reviews

• Comprehensive Enzyme System
  The simultaneous inclusion of both NADPH and UDPGA cofactors within the Creative Biolabs service provides a significant mechanistic advantage. This approach facilitated the identification of a reactive glucuronide metabolite that was previously undetected, thereby revealing a critical liability in our principal compound. - Dr. E***n Chen.
• Structural Insight
  We relied upon Creative Biolabs' LC-HRMS analysis incorporating stable isotope labeling for adduct confirmation. The ability to precisely confirm the molecular structure and elemental composition of the trapped species via the isotopic doublet proved invaluable for validating the mechanism of toxicity to our internal safety team. - Jessica H**s.

FAQs

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How to Contact Us

Creative Biolabs' reactive metabolite screening service is your essential tool for mitigating the catastrophic risk of late-stage drug attrition. By providing rapid, high-throughput, and mechanistically detailed data on reactive metabolite formation, we empower your team to optimize chemical structures for safety and accelerate the transition to preclinical study. Please contact us now.

Reference

1. Wang, Yi-Kun et al. "Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities." Frontiers in pharmacology vol. 12 758468. 20 Oct. 2021. Distributed under an Open Access license CC BY 4.0, without modification. https://doi.org/10.3389/fphar.2021.758468

For Research Use Only | Not For Clinical Use