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Metabolic Stability of Low Clearance Compounds

Sygnature’s routine hepatocyte stability assay monitors the disappearance of a substrate in suspension, over 1-2 hours incubation.  Evaluating low clearance compounds can be a challenge using existing methods.  To accurately determine intrinsic clearance and half-life values of low clearance compounds, Sygnature has developed a method utilising primary human hepatocytes in culture, enabling longer incubation times (typically 24 hours).  Data output consists of mean intrinsic clearance (Clint) and half-life (t1/2) measurements.


Compound requirements 10 mM in DMSO, 20µL
Test Article Concentration 1 µM
Hepatocyte Concentration 0.35 x 106 cells / well
Incubation Conditions Up to 24 hours at 37°C
Time Points 0, 1, 2, 4, 18, 24 hours
Analysis Method LC-MS/MS
Controls 2 Positive controls
Data Delivery Clint (µL/min/1×106 cells), Half-life (min)



Figure 1 Control compound CLint data for n=3 experiments.


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The DMPK & Physical Sciences department at Sygnature Discovery is dedicated to understanding and optimising the absorption, distribution, metabolism and excretion of drug candidates by working in close partnership with clients and other departments within Sygnature to provide successful optimisation strategies.

We have extensive know-how and expertise to provide well validated, state-of-the-art assays and a comprehensive applied consultancy service for interpretation of the in vitro ADME and in vivo PK data.

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