New Perspectives on Acyl Glucuronide Risk Assessment in Drug Discovery: Investigation of In vitro Stability, In situ Reactivity, and Bioactivation

Conclusion: While the compounds tested from “withdrawn” and “warning category” all formed the glutathione adduct in buffer, none from “safe” category formed the glutathione adduct. In contrast, none of the compounds tested from any category formed methoxylamine conjugate, a reaction with putative aldehyde moiety formed via acyl migration. These results, highly favor the nucleophilic displacement as a cause of the reactivity rather than the acyl migration via aldehyde formation. The workflow presented could also be applied in the discovery setting to triage new chemical entities of interest.
Source: Drug Metabolism Letters - Category: Drugs & Pharmacology Source Type: research