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The bile salt export pump (BSEP in humans, Bsep in animals) is a member of the ATP-binding cassette superfamily of transport proteins. BSEP is selectively located in the apical (canalicular) domain of hepatocytes and catalyzes the rate-limiting step in bile salt secretion from hepatocytes into the bile duct. Reduction of BSEP activity by chemical inhibition leads to disturbances in bile acid trafficking, hepatocellular accumulation of bile acids (intrahepatic cholestasis), and eventually to drug-induced liver injury (DILI). A compound's potential to inhibit BSEP can be assessed by means of dedicated in vitro assays using primary or transfected cells, or cell fragments containing the transport protein. Alternatively, bile salt transport inhibition can also be assessed by measuring plasma bile salt levels in vivo. This latter, more holistic approach may represent an attractive alternative as it allows for a more physiological assessment beyond the mere inhibition of the isolated BSEP transporter. The structural diversity of compounds showing significant BSEP inhibition is rather large. Unfortunately, specific structural features responsible for BSEP inhibition have not been identified so far. Results of computational structure–activity relationship (SAR) analyses indicate that increasing molecular weight and lipophilicity favour BSEP inhibition.

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