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Technical Pitfalls and Improvements for High-speed Screening and QSAR Analysis to Predict Inhibitors of the Human Bile Salt Export Pump (ABCB11/BSEP)

  • Mini-Review
  • Theme: Structure-Activity relationships for ABC Transporters
  • Published:
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Abstract

Drug-induced hepatotoxicity is one of the major problems encountered in drug discovery and development. Selection of a candidate compound for pre-clinical studies in the drug discovery process is a critical step that can determine the speed and expenditure of clinical development. Because inhibition of human adenosine triphosphate-binding cassette transporter ABCB11 (SPGP/bile salt export pump) has severe consequences, which include intrahepatic cholestasis and hepatotoxicity, resulting from exposure to toxic xenobiotics or drug interactions, in vitro screening methods are necessary for quantifying and characterizing the inhibition of ABCB11. In line with such initiatives, we developed methods for in vitro high-speed screening and quantitative structure-activity relationship (QSAR) analysis to investigate the interaction of ABCB11 with a variety of compounds. We identified one set of chemical fragmentation codes closely linked with inhibition of ABCB11. Furthermore, the high-speed screening method enables us to analyze the kinetics of ABCB11-inhibition by test compounds and to distinguish competitive and non-competitive inhibitors. Troglitazone and novobiocin were found to be competitive inhibitors to taurocholate, whereas porphyrins were non-competitive inhibitors. Kinetics-based classification of inhibitors is considered important to improve the accuracy of our QSAR analysis. The present mini-review addresses technical pitfalls and improvements for high-speed screening and QSAR analysis in the ABCB11 inhibition study.

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Acknowledgements

The study carried out in the authors’ laboratory was supported, in part, by the NEDO International Joint Research Grant program “International standardization of functional analysis technology for genetic polymorphisms of drug transporters” and research grants (No. 18201041 and No. 19659136) from the Japanese Society for Promotion of Science (JSPS). Hikaru Saito is a JSPS fellow. Under the license agreement (license number 2235670436990) with the American Chemical Society, Figs. 2 and 3 as well as Table I in the present review article have been reproduced from our previous study (26) published in Molecular Pharmaceutics.

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Authors and Affiliations

  1. Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-60, Nagatsuta, Midori-ku, Yokohama, 226-8501, Japan

    Hikaru Saito, Hiroyuki Hirano, Wangsoo Shin, Ryota Nakamura & Toshihisa Ishikawa

  2. Department of Basic Medical Sciences, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Hikaru Saito

  3. Integrated Imaging Research Support, 1-7-5 Hirakawa-cho, Chiyoda-ku, Tokyo, 102-0093, Japan

    Masako Osumi

  4. Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan

    Toshihisa Ishikawa

Authors
  1. Hikaru Saito
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  2. Masako Osumi
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  3. Hiroyuki Hirano
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  4. Wangsoo Shin
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Correspondence to Toshihisa Ishikawa.

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Guest Editor: Marilyn E. Morris

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Saito, H., Osumi, M., Hirano, H. et al. Technical Pitfalls and Improvements for High-speed Screening and QSAR Analysis to Predict Inhibitors of the Human Bile Salt Export Pump (ABCB11/BSEP). AAPS J 11, 581–589 (2009). https://doi.org/10.1208/s12248-009-9137-9

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