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Research ArticleSpecial Section on Transporters in Toxicity and Disease

Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations beyond the Direct Inhibition of the Bile Salt Export Pump

A. David Rodrigues, Yurong Lai, Mary Ellen Cvijic, Lisa L. Elkin, Tatyana Zvyaga and Matthew G. Soars
Drug Metabolism and Disposition April 2014, 42 (4) 566-574; DOI: https://doi.org/10.1124/dmd.113.054205
A. David Rodrigues
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (A.D.R., Y.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (M.S.); Leads Discovery and Optimization, Bristol-Myers Squibb, Princeton, New Jersey (M.E.C.); and Leads Discovery and Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (L.E., T.Z.)
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Yurong Lai
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (A.D.R., Y.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (M.S.); Leads Discovery and Optimization, Bristol-Myers Squibb, Princeton, New Jersey (M.E.C.); and Leads Discovery and Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (L.E., T.Z.)
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Mary Ellen Cvijic
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (A.D.R., Y.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (M.S.); Leads Discovery and Optimization, Bristol-Myers Squibb, Princeton, New Jersey (M.E.C.); and Leads Discovery and Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (L.E., T.Z.)
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Lisa L. Elkin
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (A.D.R., Y.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (M.S.); Leads Discovery and Optimization, Bristol-Myers Squibb, Princeton, New Jersey (M.E.C.); and Leads Discovery and Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (L.E., T.Z.)
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Tatyana Zvyaga
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (A.D.R., Y.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (M.S.); Leads Discovery and Optimization, Bristol-Myers Squibb, Princeton, New Jersey (M.E.C.); and Leads Discovery and Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (L.E., T.Z.)
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Matthew G. Soars
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (A.D.R., Y.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (M.S.); Leads Discovery and Optimization, Bristol-Myers Squibb, Princeton, New Jersey (M.E.C.); and Leads Discovery and Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (L.E., T.Z.)
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This article has a correction. Please see:

  • Correction to “Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations Beyond the Direct Inhibition of the Bile Salt Export Pump” - November 01, 2014

Abstract

The bile salt export pump (BSEP) is located on the canalicular plasma membrane of hepatocytes and plays an important role in the biliary clearance of bile acids (BAs). Therefore, any drug or new chemical entity that inhibits BSEP has the potential to cause cholestasis and possibly liver injury. In reality, however, one must consider the complexity of the BA pool, BA enterohepatic recirculation (EHR), extrahepatic (renal) BA clearance, and the interplay of multiple participant transporters and enzymes (e.g., sulfotransferase 2A1, multidrug resistance–associated protein 2, 3, and 4). Moreover, BAs undergo extensive enzyme-catalyzed amidation and are subjected to metabolism by enterobacteria during EHR. Expression of the various enzymes and transporters described above is governed by nuclear hormone receptors (NHRs) that mount an adaptive response when intracellular levels of BAs are increased. The intracellular trafficking of transporters, and their ability to mediate the vectorial transport of BAs, is governed by specific kinases also. Finally, bile flow, micelle formation, canalicular membrane integrity, and BA clearance can be influenced by the inhibition of multidrug resistant protein 3- or ATPase-aminophospholipid transporter–mediated phospholipid flux. Consequently, when screening compounds in a discovery setting or conducting mechanistic studies to address clinical findings, one has to consider the direct (inhibitory) effect of the parent drug and metabolites on multiple BA transporters, as well as inhibition of BA sulfation and amidation and NHR function. Vectorial BA transport, in addition to BA EHR and homoeostasis, could also be impacted by drug-dependent modulation of kinases and enterobacteria.

Footnotes

    • Received August 13, 2013.
    • Accepted October 10, 2013.
  • dx.doi.org/10.1124/dmd.113.054205.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleSpecial Section on Transporters in Toxicity and Disease

Mechanisms Leading to Drug-Induced Cholestasis

A. David Rodrigues, Yurong Lai, Mary Ellen Cvijic, Lisa L. Elkin, Tatyana Zvyaga and Matthew G. Soars
Drug Metabolism and Disposition April 1, 2014, 42 (4) 566-574; DOI: https://doi.org/10.1124/dmd.113.054205

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Research ArticleSpecial Section on Transporters in Toxicity and Disease

Mechanisms Leading to Drug-Induced Cholestasis

A. David Rodrigues, Yurong Lai, Mary Ellen Cvijic, Lisa L. Elkin, Tatyana Zvyaga and Matthew G. Soars
Drug Metabolism and Disposition April 1, 2014, 42 (4) 566-574; DOI: https://doi.org/10.1124/dmd.113.054205
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    • Abstract
    • Introduction
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    • Conclusions (Going Beyond “BSEP Bias”)
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