Assess Efflux DDI Risk

Type:Services
SUBTYPE:Hepatobiliary Disposition
APPLICATION & SPECIALITY USES:ADME-Toxicology Products and Services
Keywords:B-CLEARB-CLEAR TechnologyBiliary ClearanceBiliary ExcretionEfflux DDIHepatic Clearance

We recommend assessing the biliary disposition DDI and other interaction effects of a test article if data from transporter screening study indicates transporter-mediated efflux occurs and if an uptake rate study indicates there is active uptake.

Biliary disposition DDI studies are used for the following evaluations of a test article:

  • Evaluate the potential to inhibit biliary clearance, likely due to inhibition of the BSEP transporter.
  • Predict the potential risk of cholestatic hepatotoxicity.
  • Indicate the needs for additional BSEP inhibition studies and evaluation of cholestatic hepatotoxicity risk

Our novel B-CLEAR study method using TRANSPROTER CERTIFIED hepatocytes in sandwich culture provides superior DDI evaluations because the hepatocytes in the model have have physiologically-relevant transporter, metabolism, and regulatory function.

Deliverables

Our biliary disposition DDI studies include the following deliverables:

  • Assessment of inhibition potential of a test article on the hepatobiliary clearance of a standard probe substrate
  • Assessment of the following parameters for the probe substrate, in the presence and absence of the test article and positive control:
    • Total Accumulation (Hepatic Uptake)
    • Cellular Accumulation (Intracellular Accumulation)
    • Hepatic Accumulation (Kp): Ratio of total intracellular concentration to total dose concentration
    • Biliary Excretion Index (BEI): (Hepatic Efflux)
    • In Vitro Biliary Clearance (Clbiliary): Predictive of in vivo biliary clearance

Study Design

We adapt study protocols based on input from our clients about their test articles and research objectives. In our standard study design a probe_substrate is evaluated at a single time point and concentration in the presence of a physiological concentration of protein (4% BSA). The inhibition potential of the test article is evaluated at five concentrations. A positive control inhibitor is examined at two concentrations. A vehicle control is run in parallel. Each test condition is performed in three wells to provide triplicate data, expressed as mean ┬▒ standard deviation