Metabolic profiling processes

Many lead discovery candidates are transferred to the preclinical development process with insufficient characterization to assess their development potential. This lack of knowledge usually results in poorly designed experiments that are not data productive and that, in many cases, have to be repeated when a candidate shows unexpected toxicity, low and variable delivery, instability in formulation, or unacceptable pharmacokinetic and drug metabolism profiles. In all too many cases, the recognition of these problem areas results in termination of... 

Species Extrapolation. The Medinsky model used species-specific information to outline the model parameters little extrapolation of information between mice and rats was required. Based on the parameters derived for mice, metabolism of benzene after inhalation by humans was simulated. The results indicate that at concentrations below 10 ppm, metabolism and formation of metabolites is linearly related to inhaled concentration, and that hydroquinone conjugates are the predominant metabolite. At concentrations above 10 ppm, the model predicts a change in the metabolic profile, with increased proportion of phenyl conjugates, associated with detoxification processes. 

The fully automated computational procedure is a valuable ne v tool in virtual screening and in early ADME-Tox, vhere drug safety and metabolic profile patterns must be evaluated in order to enhance and streamline the process of developing neiv drug candidates. 

While metabolite identification studies provide critical information on drug candidates, these studies have typically been reserved for compounds late in the development phase. These studies are not amenable to high throughput as each compound will give a different metabolic profile, and evaluation of the data can be a lengthy and labor-intensive process. Traditional studies required radio labeled compounds,... 

Following collection, tissue and excreta samples are analyzed for total radioactive content and the pooled samples (by sex and/or sacrifice interval) are processed and analyzed to determine the metabolic profile of tissue and excreta radioactivity. Following profiling, major tissue and excreta metabolites are isolated and identified. 

The FDA suggests that the metabolic profile of a drug be identified during the drug development process. In vitro studies utilise liver microsomes, liver slices or hepatocytes from animals and humans before initiation of clinical trials. Results from in vivo metabolism studies should be available early in the drug development process since they confirm results from in vitro studies or reveal quantitative or qualitative differences in metabolism across species, which would cause a safety concern. Human in vivo metabolism is carried out at a later stage. 

The metabolic profiles are analyzed for qualitative or quantitative changes in individual components which might correlate with the onset of disease processes or the female reproductive cycle. 

---