Reactive metabolite formation evaluation

In a more thorough and balanced evaluation of the in vitro reactive metabolite tests in both human liver microsomes and S9 fractions, Obach et al. found that a panel of safe drugs in the clinic can form as much reactive metabolites as those hepatotoxic drugs, even after corrections for drug clearance parameters.92-93 Obviously, a more balanced and system-based approach to reactive metabolite formation and its clinical implications is needed hence forward. 

Experimental methodology to evaluate reactive metabolite formation... 

Figure 6-3 Examples of drugs evaluated for reactive metabolite formation via electrochemical...

Hemolytic anemia has been described for drugs containing sulfonamides, quinones, anilines, and carboxylic acids resulting from oxidative damage or covalent binding to red blood cells.42-49 NCEs with these functional groups should be carefully evaluated for reactive metabolite formation early in drug discovery. 

The cell culture analog (CCA) system is one approach attempting to narrow this gap. It is developed to address the issues of reactive metabolite formation and tissue-tissue interaction through exchange of metabolites or signal molecules, and to evaluate potential efficacy and toxicity of pharmaceuticals and environmental chemicals. A CCA device can be considered as a simplified and minimized human/animal body, in which mammalian cell cultures are used to represent key functions of specific organs, and cell culture medium is used as a blood surrogate. 

Another important factor to evaluate is the initial dye concentration of the azo dye-containing wastewaters. Swshadri and Bishop drew a conclusion that dye concentration may cause a drop in the percentage of dye removal. Furthermore, the inhibition may be directly related to the effects of increased dye metabolite formation due to higher dye concentrations. Cariell et al. [96] found that C.I. Reactive Red 141 was inhibitory to anaerobic organisms at concentrations greater than 100 mg/L. 

A concept that is critical in the complex evaluation of bound residues is the adduct residue. The concept of adduct residue can be applied to any metabolite covalently linked to an endogenous component. Hydrolysis of Ure macromolecular bound residue, whether by enzymatic or chemical means, may lead to lower-molecular-weight adduct residues, free residues, and residue fragments. Since bound residues are derived from reactive metabolites, the reversibility of adduct formation to yield reactive compounds may be a key factor in the safety assessment of bound residues. 

---