Continuing the theme of an earlier post, an excellent article in Current Topics in Medicinal Chemistry looks at the issue of adverse drug events associated with the formation of reactive intermediates. The authors (from Novartis) give some background to drug-related idiosyncratic toxicity and the link to covalent binding by active metabolites (usually electrophiles or free radicals) of drug molecules. The possible mechanisms of toxicity (e.g. inactivation of enzymes, disruption of calcium homeostasis, disruption of membranes, the hapten hypothesis, etc.) are briefly discussed and then the main body of the paper focuses on practical strategies for minimizing these risks. This section is organised as outlined below:
- Structural Alerts – A comprehensive listing of documented alerts and referenced chemical intervention strategies (including partial or complete substitution of structure, addition of steric bulk, reduction of electron density, metabolic switching, and isosteric replacement).
- In Silico Approaches – A brief look at modern software approaches to identifying and managing active metabolite risks (e.g. Metasite®, Metadrug®, Isentris®, Meteor®)
- Assaying Reactive Metabolite Risk – An overview of the various in vitro (i.e. use of nucleophilic trapping agents and the assessment of covalent protein binding potential) and in vivo methods which are routinely used to assay the formation of adducts of drug-related metabolites.
- Bioactivation in the Context of Drug Discovery – A short section covering the interpretation of bioactivation and reactive metabolite data and the assessment of the associated clinical risk (i.e. dosage, usage, detoxification, metabolic route, route of administration).
- Future Directions and Approaches
The article is well researched and presented and should serve as a useful and practical guide to this challenging aspect of drug design.