Cholestatic Hepatotoxicity

DPZCHOL

Type:Services
SUBTYPE:Hepatotoxicity
SPECIES:
APPLICATION & SPECIALITY USES:ADME-Toxicology Products and Services
Keywords:Cholestasis Y17C-DILI AssyCholestatic Hepatotoxicity

OPTIONS:

We use the novel C-DILI™ Assay and TRANSPORTER CERTIFIED™ human hepatocytes to evaluate a compound’s potential for cholestatic drug-induced liver injury (DILI).

The C-DILI Assay has demonstrated high in vitro – in vivo correlation with compounds known to have a risk of cholestatic hepatotoxicity. It is an effective tool for assessing the risk of cholestatic DILI and providing data useful in lead selection and managing toxicity risk.

At high concentrations, bile acids can cause liver toxicity by signaling apoptotic pathways as well as disrupting membranes. Bile acid concentrations in the liver are tightly controlled through multiple regulatory mechanisms including canalicular and basolateral efflux, synthesis, and metabolism. However, if control mechanisms are disrupted, bile acid concentrations can reach a “tipping point” resulting in hepatotoxicity. The C-DILI Assay combines all of these human-relevant processes in one simple threshold readout, providing a unique clinically-predictive assessment of cholestasis risk.

Our Process

TRANSPORTER CERTIFIED hepatocytes are cultured in a 96-well sandwich-culture format to reestablish physiologically-relevant uptake, metabolism, regulation and efflux function. The hepatocytes form a matrix with bile pockets and demonstrate transporter function, including BSEP, OSTs, and MRP3/4. After the culture has been established, our proprietary QUALGRO™ Sensitization Media is added to the wells, along with the test compound, and incubated for 24 hours. Cholestatic hepatotoxicity is evaluated by measuring lactate dehydrogenase (LDH) concentration and ATP content versus controls in a standard plate-reader assay.

The response of the test article is compared to drugs with known clinical cholestatic effects. Comparison with negative controls and positive controls allow compounds to be bucketed for their clinical cholestatic hepatotoxicity potential. In addition, an incubation without the QUALGRO Sensitization Media can be performed in parallel to assess hepatotoxicity directly from the compound.

Study Report

The C-DILI Assay report is an easy-to-read assessment of LDH secretion and ATP content as a % of solvent control, and compared to negative and positive control standards. Test compounds are coded as green, orange, or red, for low, medium or high risk of cholestatic DILI potential.

Accelerate Decision-Making

Either as a stand-alone program or implemented with other studies the C-DILI Assay is designed to complement your R&D process. From early stage screening through optimization
and characterization and through clinical development  the C-DILI Assay informs SAR, lead selection, and toxicity assessment programs.