High-Speed Screening and QSAR Analysis of Human ATP-Binding Cassette Transporter ABCB11 (Bile Salt Export Pump) To Predict Drug-Induced Intrahepatic Cholestasis

Abstract

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-dependent transport of [14C]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.

Flagging Drugs That Inhibit the Bile Salt Export Pump

“…Hirano et al 8 tested 42 compounds among neurotransmitters, calcium channel blockers, potassium channel modulators, steroids, non-steroidal anti-inflammatory drugs, anticancer drugs, and others. The percentage of inhibition of BSEP at 100 µM was measured (in comparison with a negative control without test drug).…”

“…Since we used a threshold of 10 µM to define an active in the training set, we count both results as false positives. Tamoxifen and nelfinavir are inconsistently reported with both inhibitor and non-inhibitor activities 8,16,10,13 . This leaves us with 32 compounds that are top ranked and for which we could not find any pharmacological annotation regarding BSEP.…”

“…Another 18 compounds had IC 50 values over 10 µM but below 50 µM, and as such do not strictly count as errors 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 since we used 10 µM as a threshold to define the inhibitors in the training set. Finally, six compounds were mispredicted as non-inhibitors while they were actually reported as inhibitors: atazanavir 10,23 , telithromycin 8,16 , ranolazine 10 , trovafloxacin 23 , pioglitazone 13,9,16 and diethylstilbestrol 10 . This results in 161 true negatives and 6 false negatives, which corresponds to a negative predictive value of 96% (the negative predictive value is obtained by dividing the number of true negatives by the total number of predicted negatives).…”

The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation

“…These findings will be discussed in the following section. Recently, a first report of findings on quantitative structure-activity relationship analysis using BSEP inhibitors has been published [123].…”

Recent insights into the function and regulation of the bile salt export pump (ABCB11)

“…A first report on quantitative structure-activity relationship of inhibitors of BSEP has been published (81). Hence, it can be expected that more information on the structural requirements of BSEP inhibitors will become available.…”