Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis ofdrugs inhibiting the human bile salt export pump

Abstract

Drug-induced intrahepatic cholestasis is one of the major causes of hepatotoxicity, which often occur during the drug discovery and development process. Human ATP-binding cassette transporter ABCB11 (sister of P-glycoprotein/bile salt export pump) mediates the elimination of cytotoxic bile salts from liver cells to bile, and, therefore, plays a critical role in the generation of bile flow. The authors have recently developed in vitro high-speed screening and quantitative structure–activity relationship analysis methods to investigate the interaction of ABCB11 with a variety of compounds. Based on the extent of inhibition of the bile salt export pump, the authors analysed the quantitative structure–activity relationship to identify chemical groups closely associated with the inhibition of ABCB11. This approach provides a new tool to predict compounds with a potential risk of drug-induced intrahepatic cholestasis.

Keywords::

• ABCB11
• ABC transporter
• bile salt
• intrahepatic cholestasis
• troglitazone

Acknowledgements

The study carried out in the authors’ laboratory was supported, in part, by the NEDO International Joint Research Grant programme ‘International standardisation of functional analysis technology for genetic polymorphisms of drug transporters’ and a research grant (No. 18201041) from the Ministry of Education, Science, Technology, Sports, and Culture of Japan.