The main metabolic site of the drug is the liver. Liver-derived systems, such as liver slices, subcellular liver fractions, and intact hepatocytes are typically used to assess the metabolism of new chemical entities (NCEs). Hepatocytes, having an intact cell membrane and physiological concentrations of phase I and phase II enzymes in addition to cofactors, are generally considered to be the most accurate model for predicting whole liver drug clearance. NCEs can be screened and prioritized based on estimates of metabolic half-life or intrinsic clearance values obtained from metabolic stability studies. Moreover, hepatocyte metabolic screening assays allow drug developers to focus on the improvement of compounds through structural-activity relationships and prevent the progression of labile compounds to more costly in vivo research.
Creative Bioarray's hepatocyte stability assay monitors the disappearance of substrates in the presence and absence of hepatocytes. This assay can determine the fate of the drug in the body and calculate its clearance rate. Using hepatocytes from a variety of species, we can help determine the species-specificity of hepatic clearance and translate animal data to the human scenario.
Hepatocyte Metabolic Stability
Hepatocyte concentration
500,000 cells/mL
Test compound concentration
1 µM
Time points
0, 5, 15, 30, 45, 60, 90, 120 minutes
Assay controls
Positive control: Testosterone, Ethoxycoumarin, or Midazolam
Negative control with vehicle
Number of replicates
3
Analysis method
LC-MS/MS
Data delivery
Intrinsic clearance (CLint)
Half-life (t1/2)
%Disappearance of parent compound
Compound requirements
200 µL 10 mM stock in DMSO
Species
Human, monkey, minipig, dog, rabbit, rat, mouse
References
- Cassim S. et al.; From in vivo to in vitro: Major metabolic alterations take place in hepatocytes during and following isolation. PLOS ONE, 2017, 12(12): e0190366.
- Di L. et al.; Mechanistic insights from comparing intrinsic clearance values between human liver microsomes and hepatocytes to guide drug design. European Journal of Medicinal Chemistry, 2012, 57: 441-448.
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