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Research ArticleArticle

Sacubitril Is Selectively Activated by Carboxylesterase 1 (CES1) in the Liver and the Activation Is Affected by CES1 Genetic Variation

Jian Shi, Xinwen Wang, Jenny Nguyen, Audrey H. Wu, Barry E. Bleske and Hao-Jie Zhu
Drug Metabolism and Disposition April 2016, 44 (4) 554-559; DOI: https://doi.org/10.1124/dmd.115.068536
Jian Shi
Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
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Xinwen Wang
Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
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Jenny Nguyen
Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
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Audrey H. Wu
Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
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Barry E. Bleske
Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
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Hao-Jie Zhu
Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
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Abstract

Sacubitril was recently approved by the Food and Drug Administration for use in combination with valsartan for the treatment of patients with heart failure with reduced ejection fraction. As a prodrug, sacubitril must be metabolized (hydrolyzed) to its active metabolite sacubitrilat (LBQ657) to exert its intended therapeutic effects. Thus, understanding the determinants of sacubitril activation will lead to the improvement of sacubitril pharmacotherapy. The objective of this study was to identify the enzyme(s) responsible for the activation of sacubitril, and determine the impact of genetic variation on sacubitril activation. First, an incubation study of sacubitril with human plasma and the S9 fractions of human liver, intestine, and kidney was conducted. Sacubitril was found to be activated by human liver S9 fractions only. Moreover, sacubitril activation was significantly inhibited by the carboxylesterase 1 (CES1) inhibitor bis-(p-nitrophenyl) phosphate in human liver S9. Further incubation studies with recombinant human CES1 and carboxylesterase 2 confirmed that sacubitril is a selective CES1 substrate. The in vitro study of cell lines transfected with wild-type CES1 and the CES1 variant G143E (rs71647871) demonstrated that G143E is a loss-of-function variant for sacubitril activation. Importantly, sacubitril activation was significantly impaired in human livers carrying the G143E variant. In conclusion, sacubitril is selectively activated by CES1 in human liver. The CES1 genetic variant G143E can significantly impair sacubitril activation. Therefore, CES1 genetic variants appear to be an important contributing factor to interindividual variability in sacubitril activation, and have the potential to serve as biomarkers to optimize sacubitril pharmacotherapy.

Footnotes

    • Received December 1, 2015.
    • Accepted January 20, 2016.
  • Research reported in this publication was supported in part by the National Institutes of Health National Center for Advancing Translational Sciences [Grant 2UL1TR000433], National Institute on Aging [Grant R21AG048500], and American Association of Colleges of Pharmacy 2015 New Investigator Award.

  • dx.doi.org/10.1124/dmd.115.068536.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (4)
Drug Metabolism and Disposition
Vol. 44, Issue 4
1 Apr 2016
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Research ArticleArticle

Sacubitril Activation Is Governed by Hepatic CES1

Jian Shi, Xinwen Wang, Jenny Nguyen, Audrey H. Wu, Barry E. Bleske and Hao-Jie Zhu
Drug Metabolism and Disposition April 1, 2016, 44 (4) 554-559; DOI: https://doi.org/10.1124/dmd.115.068536

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Research ArticleArticle

Sacubitril Activation Is Governed by Hepatic CES1

Jian Shi, Xinwen Wang, Jenny Nguyen, Audrey H. Wu, Barry E. Bleske and Hao-Jie Zhu
Drug Metabolism and Disposition April 1, 2016, 44 (4) 554-559; DOI: https://doi.org/10.1124/dmd.115.068536
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