A plethora of studies using genetically modified animals and humans with genetic diseases have highlighted the key role that transporters play in the homeostasis of both bile acids and bilirubin. To this end, inhibition of the bile salt export pump (BSEP) and the multidrug resistance protein 2 (MRP2) have been implicated as a major cause of cholestasis and conjugated hyperbilirubinemia respectively. This has prompted the pharmaceutical industry and regulators alike to focus considerable effort on screening new chemical entities (NCEs) against these potential liabilities. In reality, the disposition of both bile acids and bilirubin is mediated by a complex interplay between multiple transporters and enzymes. Differences in physiology and transporter function between the pre-clinical species and humans further hamper our efforts in this area. This presentation will highlight both the available tools and how to apply them pre-clinically to derisk the potential of NMEs to cause hepatotoxicity.

Role of transporters in cholestasis and conjugated hyperbilirubinemia

248th National Meeting (2014)

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