The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids into the bile canaliculi. The most compelling evidence linking dysfunction in bile acid transport with liver injury in humans is found with carriers of mutations that render BSEP non-functional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans, however causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (Css) for each of these annotated drugs was estimated, and a ratio between this value and measured IC50 potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a Css/BSEP IC50 ratio = 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRP) believed to play a role in bile acid homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function were also evaluated in membrane vesicle assays. Drugs with a Css/BSEP IC50 ratio = 0.1 and a Css/MRP IC50 ratio = 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP, but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered bile acid transport.

Multifactorial approach to hepatobiliary transporter assessment enables improved hazard identification

248th National Meeting (2014)

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