Toxicity off-target

Compound related includes drug metabolism and pharmacokinetics (DMPK), safety (off-target toxicity) and selectivity, and formulation and synthesis (cost of goods)... 

A number of commercial antibody-based microarrays for multiplexed cytokines analysis are now available (Beckman Coulter BD Biosciences Panom-ics Pierce S S Zyomyx and others). Cytokines are essentially biomarkers of cell injury, inflammation, and apoptosis. They are released by cells in culture in response to drug action (Turtinen et al., 2004) or are elevated in serum in various disease states. Moreover, numerous cytokines are involved in cellular response and many serve as dual effectors (Asao and Fu, 2000). As a result, anticytokine microarrays are being evaluated in drug discovery for off-target toxicity testing to replace standard ELISA plate formats. 

GEM models can be useful in identifying off-target toxicities (Figure 14.2). If a knockout does not have an adverse phenotype, but the compound has an adverse effect, then the compound can be tested in the knockout model. If the adverse effect is seen in the knockout, that is, in the absence of the intended target, then the effect must be off target. 

On this basis, the proteins of riboflavin biosynthesis may be relevant targets for the development of novel antibacterial agents, notably with selectivity for mycobacteria, Enterobacteriaceae, or pathogenic yeasts. Since these proteins are absent in human and animal hosts, the risks of off-target toxicity should be comparatively low. 

Toxicological effects May be related to metabolite and unrelated to pharmacology Generally associated with pharmacology or immunogenicity On-/off-target toxicity related to MOA of cytotoxic warhead... 

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