Journal
MOLECULAR PHARMACEUTICS
Volume 3, Issue 3, Pages 252-265Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp060004w
Keywords
ABC transporter; ABCB11; bile salt; intrahepatic cholestasis; troglitazone
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Human ATP-binding cassette transporter ABCB11 (SPGP/BSEP) mediates the elimination of bile salts from liver cells and thereby plays a critical role in the generation of bile flow. In the present study, we have developed in vitro high-speed screening and quantitative structure-activity relationship (QSAR) analysis methods to investigate the interaction of ABCB11 with a variety of drugs. Plasma membrane vesicles prepared from insect cells overexpressing human ABCB11 were used to measure the ATP-depenclent transport of [C-14]taurocholate. Over 40 different drugs and natural compounds were tested to evaluate their interaction with ABCB11 mediated taurocholate transport. On the basis of the extent of inhibition, we have analyzed the QSAR to identify one set of chemical fragmentation codes closely associated with the inhibition of ABCB11. This approach can be used to predict compounds with a potential risk of drug-induced intrahepatic cholestasis.
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