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Expert Opin Drug Metab Toxicol. 2014 Apr;10(4):581-97. doi: 10.1517/17425255.2014.884069. Epub 2014 Mar 4.

Hepatobiliary transporters in drug-induced cholestasis: a perspective on the current identifying tools.

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  • 1Faculdade de Farmácia - UFMG, Departamento de Análises Clínicas e Toxicológicas, Av. Antônio Carlos, 6.627 - Pampulha, 31270-901 - Belo Horizonte - MG , Brazil +55 31 3547 3462 ;



Impaired bile formation leads to the accumulation of cytotoxic bile salts in hepatocytes and, consequently, cholestasis and severe liver disease. Knowledge of the role of hepatobiliary transporters, especially the bile salt export pump (BSEP), in the pathogenesis of cholestasis is continuously increasing.


This review provides an introduction into the role of these transport proteins in bile formation. It addresses the clinical relevance and pathophysiologic consequences of altered functions of these transporters by genetic mutations and drugs. In particular, the current practical aspects of identification and mitigation of drug candidates with liver liabilities employed during drug development, with an emphasis on preclinical screening for BSEP interaction, are discussed.


Within the potential pathogenetic mechanisms of acquired cholestasis, the inhibition of BSEP by drugs is well established. Interference of a new compound with BSEP transport activity should raise a warning sign to conduct follow-up experiments and to monitor liver function during clinical development. A combination of in vitro screening for transport interaction, in silico predicting models, and consideration of physicochemical and metabolic properties should lead to a more efficient screening of potential liver liability.

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