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Research ArticleArticle

Mitigating the Inhibition of Human Bile Salt Export Pump by Drugs: Opportunities Provided by Physicochemical Property Modulation, In Silico Modeling, and Structural Modification

Daniel J. Warner, Hongming Chen, Louis-David Cantin, J. Gerry Kenna, Simone Stahl, Clare L. Walker and Tobias Noeske
Drug Metabolism and Disposition December 2012, 40 (12) 2332-2341; DOI: https://doi.org/10.1124/dmd.112.047068
Daniel J. Warner
Department of Medicinal Chemistry, AstraZeneca R&D Montreal, Montreal, Quebec, Canada (D.J.W., L.-D.C.); Computational Sciences, Discovery Sciences (H.C.), and Global Safety Assessment (T.N.), AstraZeneca R&D Mölndal, Mölndal, Sweden; and Molecular Toxicology, Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.G.K., S.S., C.L.W.)
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Hongming Chen
Department of Medicinal Chemistry, AstraZeneca R&D Montreal, Montreal, Quebec, Canada (D.J.W., L.-D.C.); Computational Sciences, Discovery Sciences (H.C.), and Global Safety Assessment (T.N.), AstraZeneca R&D Mölndal, Mölndal, Sweden; and Molecular Toxicology, Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.G.K., S.S., C.L.W.)
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Louis-David Cantin
Department of Medicinal Chemistry, AstraZeneca R&D Montreal, Montreal, Quebec, Canada (D.J.W., L.-D.C.); Computational Sciences, Discovery Sciences (H.C.), and Global Safety Assessment (T.N.), AstraZeneca R&D Mölndal, Mölndal, Sweden; and Molecular Toxicology, Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.G.K., S.S., C.L.W.)
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J. Gerry Kenna
Department of Medicinal Chemistry, AstraZeneca R&D Montreal, Montreal, Quebec, Canada (D.J.W., L.-D.C.); Computational Sciences, Discovery Sciences (H.C.), and Global Safety Assessment (T.N.), AstraZeneca R&D Mölndal, Mölndal, Sweden; and Molecular Toxicology, Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.G.K., S.S., C.L.W.)
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Simone Stahl
Department of Medicinal Chemistry, AstraZeneca R&D Montreal, Montreal, Quebec, Canada (D.J.W., L.-D.C.); Computational Sciences, Discovery Sciences (H.C.), and Global Safety Assessment (T.N.), AstraZeneca R&D Mölndal, Mölndal, Sweden; and Molecular Toxicology, Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.G.K., S.S., C.L.W.)
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Clare L. Walker
Department of Medicinal Chemistry, AstraZeneca R&D Montreal, Montreal, Quebec, Canada (D.J.W., L.-D.C.); Computational Sciences, Discovery Sciences (H.C.), and Global Safety Assessment (T.N.), AstraZeneca R&D Mölndal, Mölndal, Sweden; and Molecular Toxicology, Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.G.K., S.S., C.L.W.)
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Tobias Noeske
Department of Medicinal Chemistry, AstraZeneca R&D Montreal, Montreal, Quebec, Canada (D.J.W., L.-D.C.); Computational Sciences, Discovery Sciences (H.C.), and Global Safety Assessment (T.N.), AstraZeneca R&D Mölndal, Mölndal, Sweden; and Molecular Toxicology, Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.G.K., S.S., C.L.W.)
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Abstract

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. BSEP activity therefore plays an important role in bile flow. In humans, genetically inherited defects in BSEP expression or activity cause cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo. These findings suggest that inhibition of BSEP activity by drugs could be one of the mechanisms that initiate human DILI. To gain insight into the chemical features responsible for BSEP inhibition, we have used a recently described in vitro membrane vesicle BSEP inhibition assay to quantify transporter inhibition for a set of 624 compounds. The relationship between BSEP inhibition and molecular physicochemical properties was investigated, and our results show that lipophilicity and molecular size are significantly correlated with BSEP inhibition. This data set was further used to build predictive BSEP classification models through multiple quantitative structure-activity relationship modeling approaches. The highest level of predictive accuracy was provided by a support vector machine model (accuracy = 0.87, κ = 0.74). These analyses highlight the potential value that can be gained by combining computational methods with experimental efforts in early stages of drug discovery projects to minimize the propensity of drug candidates to inhibit BSEP.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.047068.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    DILI
    drug-induced liver injury
    BSEP
    human bile salt export pump
    ABC
    ATP-binding cassette
    Bsep
    nonhuman bile salt export pump
    DMSO
    dimethyl sulfoxide
    QSAR
    quantitative structure-activity relationship
    RP
    recursive partitioning
    PLS
    partial least squares.

  • Received June 4, 2012.
  • Accepted September 7, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (12)
Drug Metabolism and Disposition
Vol. 40, Issue 12
1 Dec 2012
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Research ArticleArticle

INHIBITION OF HUMAN BILE SALT EXPORT PUMP BY DRUGS

Daniel J. Warner, Hongming Chen, Louis-David Cantin, J. Gerry Kenna, Simone Stahl, Clare L. Walker and Tobias Noeske
Drug Metabolism and Disposition December 1, 2012, 40 (12) 2332-2341; DOI: https://doi.org/10.1124/dmd.112.047068

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Research ArticleArticle

INHIBITION OF HUMAN BILE SALT EXPORT PUMP BY DRUGS

Daniel J. Warner, Hongming Chen, Louis-David Cantin, J. Gerry Kenna, Simone Stahl, Clare L. Walker and Tobias Noeske
Drug Metabolism and Disposition December 1, 2012, 40 (12) 2332-2341; DOI: https://doi.org/10.1124/dmd.112.047068
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