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.
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
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