Metabolic Stability

• In vitro metabolism in hepatocytes, liver microsomes, S9, recombinant enzymes or extrahepatic tissues, a co-culture model for low clearance compounds
• Half-life, in vitro clearance
• In vivo extrapolation (to predict hepatic clearance & extraction ratio)

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 metabolism. For low clearance compounds, a co-culture model can be applied for investigating metabolic stability over several days.

When measuring the disappearance rate of a compound under linear velocity conditions in vitro, the results can be further extrapolated to in vivo hepatic clearance and extraction ratio, and also to evaluate the effect of hepatic first-pass metabolism to total oral bioavailability. When using UPLC/high-resolution-MS for sample analysis, also metabolite identification can be easily delivered from the same analytical data.