Short-lived reactive metabolites/intermediates

As a result of their high reactivity, reactive metabolites are often considered to be short-lived. This is not always true, however, because reactive intermediates can be transported from one tissue to another, where they may exert their deleterious effects. Thus reactive intermediates can be divided into several categories depending on their half-life under physiological conditions and how far they may be transported from the site of activation. 

Most reactive metabolites are electrophiles that react with compounds that contain nitrogen or sulfur atoms. These reactive species are generally short-lived and highly unstable. Therefore, analysis and detection is challenging. The approach that is currently used to characterize reactive metabolites in drug discovery involves the use of trapping agents that form stable adducts with the reactive intermediates [95],... 

Epoxides are not only key intermediates in several biosyntiieses they are also present in a number of secondary metabolites (Fig. 5). Again, the high reactivity of the epoxy moiety contributes to the bioactivity of these metabolites. This reactivity ensures short half-lives of metabolites, e.g., in juvenile hormones, pheromones, or the toxicity of some antibiotics. The methyl ester of 10,11-epoxyfamesenate 18 is a juvenile hormone synthesized by many insects. The pheromone disparlure 19 (see also Chapter 3 in this book) formed by the gypsy moth Lymantria dispar is active in only one enantiomeric form [8],... 

FDA s guidance on safety testing on drug metabolites (Food and Drug Administration, 2008), Metabolites that form chemically reactive intermediates can be difficult to detect and measure because of their short half-lives. However, they can form stable products (e.g., glutathione conjugates) that can be measured and, therefore, may eliminate the need for further evaluation. ... 

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