Metabolic Stability

Accurate prediction of hepatic intrinsic clearance of new chemical entities is important in progressing potential drug candidates during drug discovery. Our experienced scientists support you in all phases, from the choice of assay design to the prediction of pharmacokinetics, employing in vitro in vivo extrapolation (IVIVE).

The intrinsic hepatic clearance, which reflects the inherent ability of hepatocytes or other subcellular systems (e.g., microsomes, S9 fractions) to eliminate unbound drugs, is governed by the activity of metabolizing enzymes. The reliable and precise scaling-up of in vitro clearance is indispensable for the prediction of drug exposure and the projection of dose, half-life, and bioavailability in vivo in human and preclinical species.

Our metabolic stability assay is run on a fully automated robotic system, allowing for high compound throughput and rapid turnaround times. The assay can be performed using hepatocytes or liver microsomes from humans and various animal species, including mouse, rat, monkey, and dog. Depending on your needs, pharmacokinetic parameters, such as the compound half-life (t1/2) and in vitro intrinsic clearance (CLint), can be reported. Additionally, the intrinsic clearance in human hepatocytes can be used to predict the human hepatic blood clearance by applying the well-stirred liver model and the maximum achievable bioavailability (% Fmax). Finally, our special 4-hour long incubation and CYP3A4 fraction metabolized assays in human hepatocytes are available upon request.

Our assay is conducted with unlabeled small molecule compounds using cryopreserved hepatocytes in suspension. Quantification is performed using liquid-chromatography tandem mass spectrometry or high-resolution mass spectrometry with a possibility of offering metabolite identification.