Metabolic stability and metabolite identification & profiling

Measuring the metabolic stability of a compound in vitro provides an estimate regarding its stability, and thus elimination rate by metabolism in the body. Hepatic clearance is the most important parameter when assessing metabolic stability, and the most common approaches for its prediction are in vitro assays using liver microsomes or hepatocytes; the former focusing mainly on oxidative (CYP-mediated) metabolism, and the latter also on conjugative drug metabolism. Metabolite identification and profiling are relevant in several stages of drug discovery & development. Optimization of metabolic clearance requires information on the main metabolically labile “soft-spots” and their further chemical modification. Selection of suitable animal species for toxicity studies is facilitated by the prediction of species with most similar metabolite profiles with respect to human (first in vitro and then in vivo). The correct evaluation of metabolic enzymes involved in clearance also requires identification of the metabolites, and eventually the metabolic clearance routes in human in vivo has to be characterized in a detailed level.