Metabolite predictors

Chemistry-based toxicity also involves exposure response, individual variability, and altered clearance. However, the proximal toxicant is typically a reactive chemical species. Several current systems are used for this purpose, such as mutagenicity (see Chapter 14) and carcinogenicity software programs, fragment-based chemistry and biology predictors, adduct determinations, and metabolite predictors. 

TNF-a is considered the primary mediator of sepsis, and concentrations are elevated early in the inflammatory response during sepsis, and there is a correlation with severity of sepsis. TNF-a release leads to activation of other cytokines associated with cellular damage and it stimulates release of arachidonic acid metabolites that contribute to endothelial cell damage. IL-6 is a more consistent predictor of sepsis as it remains elevated for longer periods of time than does TNF-a. 

The stoichiometric matrix N is one of the most important predictors of network function [50,61,63,64,68] and encodes the connectivity and interactions between the metabolites. The stoichiometric matrix plays a fundamental role in the genome-scale analysis of metabolic networks, briefly described in Section V. Here we summarize some formal properties of N only. 

From a purely pragmatic perspective, it is clear that reactive metabolites are linked with toxicity and that a circumstantial link can be made to idiosyncratic toxicides. Consequently, even though the mechanism of this toxicity is not fully understood, since assays are available to measure the potential for bioactivation in an ideal world one would not carry this liability forward. Conversely, it is not an ideal world, all drug molecules have challenges and the definition of therapeutic index (i.e., the ratio between the toxic exposure and the therapeutic exposure) is critical. Covalent binding of reactive metabolites to macromolecules is a crude measure and not a full predictor of toxicity and it is well known that toxicity can be ameliorated by a lower dose. Furthermore, the so-called definitive assays require radiolabeled drug material which is expensive and generally slow to produce. 

Are Reactive Metabolite Trapping and Covalent Binding Studies Reliable Predictors of Hepatotoxic Potential of Drug Candidates ... 

Walker and Heinzow (1998), but Becker et al. (2004b) reported that permethrin in house dust was one of the significant predictors of pyrethroid metabolites in the urine of children. 

Reichardt, P.B., Chapin, F.S., III, Bryant, J.P., Mattes, B.R., and Clausen, T.P., Carbon/nutrient balance as a predictor of plant defense in Alaskan balsam poplar potential importance of metabolite turnover, Oecologia, 88, 401, 1991. 

Knowledge about metabolites and their activity is further an important criteria for the assessment of species-specific effects and differences, e.g. the search for the most human-like test model as the best predictor for human reactions, focuses on such differences. Metabolism can lead to pharmacologically active metabolites such knowledge is desirable early in development. In vitro metabolism studies normally precede in vivo preclinical safety assessments. 

ARE REACTIVE METABOLITE TRAPPING AND COVALENT BINDING STUDIES RELIABLE PREDICTORS OF TOXICITY POTENTIAL OF DRUG CANDIDATES ... 

We expect that the task lists represented by some of the boxes will increase. For example, within the box including in vitro intrinsic clearance , there may be in vitro predictors of oral availability and measures of potentially toxic metabolites. The in vivo pharmacokinetics in rats may include an increasing number of compartments whose concentrations are measured by microdialysis and may include measures of a few selected metabolite concentrations. 

High local concentrations of free drug at the on- or-off target proteins may occur due to the transport of a drug molecule (or metabolite). In almost all cases such drugs have defined physicochemical characteristics. In contrast to the compounds described in the section on basicity, lipophilicity, and volume of distribution as predictors of toxicity, the likelihood... 

Kalgutkar AS, Didiuk MT. Structural alerts, reactive metabolites, and protein covalent binding How reliable are these attributes as predictors of drug toxicity Chem Biodivers 2009 6(11) 2115-2137. 

---