Related Experiment Video
Updated: Jun 7, 2026
Monitoring On-Target Signaling Responses in Larval Zebrafish - Z-REX Unmasks Precise Mechanisms of Electrophilic Drugs and Metabolites
Published on: June 2, 2023
An integrated reactive metabolite evaluation approach to assess and reduce safety risk during drug discovery and
Melinda Reese1, Melanie Sakatis, Jeffrey Ambroso
1GlaxoSmithKline, Drug Metabolism and Pharmacokinetics, Research Triangle Park, NC, USA. mindy.j.reese@gsk.com
Abstract:
Metabolic bioactivation is widely considered an undesirable event and a likely prerequisite step in the expression of drug-induced hepatotoxicity and hypersensitivity. Reducing bioactivation risk early in drug discovery, therefore, may help reduce compound attrition and provide safer drug therapies. In vitro bioactivation data and clinical dose for a large set of marketed drugs were analysed for their concordance with clinical hepatotoxicity and the data used to develop an early reactive metabolite strategy. A contingency table analysis of cytochrome P450 metabolism-dependent inhibition (CYP MDI), glutathione trapping data, and dose for >200 marketed drugs with or without a clinical hepatotoxic signal; and microsomal covalent binding data and dose for ∼60 marketed compounds obtained from literature publications was performed to assess concordance with hepatotoxicity. Clinical daily dose ≥100mg or glutathione adduct formation was strongly associated with hepatotoxicity (p<0.0001, p=0.003, respectively). A trend towards clinical hepatotoxicity was observed with marked CYP MDI or metabolism-dependent covalent binding ≥200pmol/mg. The percentage of hepatotoxic drugs identified by high dose (67%) increased significantly when bioactivation data were combined with dose (80-100%). As CYP MDI and glutathione adduct assays do not require the synthesis of radiolabelled compound and are relatively easy to conduct, they may be of particular value for early assessment in programs with lower risk tolerance. Such information together with an overall understanding of the metabolic properties of the compound and risk/benefit considerations may trigger further assessment. Additionally hepatic transcriptomic data (e.g., Nrf2-activated gene expression) from rat toxicity studies can provide evidence of in vivo consequences of bioactivation. As attenuation of a metabolic bioactivation risk early in drug discovery could reduce compound attrition and provide safer drug therapies, we have developed a decision-based early reactive metabolite strategy that can be tailored to the needs of individual programs.
Insights
Reducing drug bioactivation risk early in drug discovery is crucial for safer therapies. Combining in vitro bioactivation data with clinical dose effectively predicts drug-induced hepatotoxicity, improving safety assessments.
Area of Science:
- Drug Discovery and Development
- Toxicology
- Medicinal Chemistry
Background:
- Metabolic bioactivation is a key factor in drug-induced liver injury and hypersensitivity.
- Early identification and mitigation of bioactivation risks can reduce compound attrition and enhance drug safety.
Purpose of the Study:
- To analyze the concordance between in vitro bioactivation data, clinical dose, and clinical hepatotoxicity for marketed drugs.
- To develop an early reactive metabolite strategy for safer drug development.
Main Methods:
- Contingency table analysis of cytochrome P450 metabolism-dependent inhibition (CYP MDI), glutathione trapping, and microsomal covalent binding data with clinical dose and hepatotoxicity for marketed drugs.
- Utilized data from >200 drugs for CYP MDI and glutathione trapping, and ~60 drugs for covalent binding.
Main Results:
- Clinical daily dose ≥100mg and glutathione adduct formation were strongly associated with hepatotoxicity (p<0.0001, p=0.003).
- Combining bioactivation data with dose significantly increased the identification of hepatotoxic drugs from 67% to 80-100%.
- CYP MDI and glutathione adduct assays are valuable, accessible tools for early risk assessment.
Conclusions:
- Integrating bioactivation assays (CYP MDI, glutathione trapping) with clinical dose provides a robust strategy for early prediction of drug-induced hepatotoxicity.
- This approach can significantly reduce compound attrition and lead to safer drug therapies.
- Hepatic transcriptomic data can offer further in vivo validation of bioactivation consequences.
Related Concept Videos
01:17Drug Metabolism: Phase I Reactions
01:28Structure-Activity Relationships and Drug Design
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence its...
01:19Pharmacovigilance
This process, termed pharmacovigilance, aims to detect, evaluate, and minimize harmful effects related to medication use. The data collection for pharmacovigilance depends on spontaneous reporting systems, where healthcare professionals or patients voluntarily report suspected ADRs.
In some cases, there...
01:27Phase I Reactions: Reductive Reactions
01:23Types of Biopharmaceutical Studies: Controlled and Non-Controlled Approaches
Non-controlled studies, commonly employed for initial exploration, lack a control group, rendering them susceptible to biases and external influences. In contrast, controlled...
01:26Drug Discovery: Overview