There is increased emphasis from regulatory agencies on measuring the propensity of drugs to inhibit drug transporters. One of these transporters is the Bile Salt Efflux Pump (BSEP). Inhibition of bile salt transport can be assessed in inside-out membrane vesicles. Since it is unclear how significant findings from this system are from a drug-bile salt interaction perspective, we developed a long term human hepatocyte co-culture system as a holistic approach to monitor the effect of compounds on the transport of bile salts. Evaluation of various BSEP inhibitors in hepatocytes demonstrated inhibition of biliary efflux, but for others no effect was observed. In some cases discrepancies could be explained by rapid metabolism. For other compounds, a change in BSEP mRNA level was observed. How to extrapolate these findings to humans is unclear. In conclusion, a risk assessment for drug-bile salt interactions based on in vitro data is difficult at present.

Approaches to study bile salt transport inhibition in vitro:  What are the data telling us?

248th National Meeting (2014)

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