2. Academic Validation
  3. Sacubitril Is Selectively Activated by Carboxylesterase 1 (CES1) in the Liver and the Activation Is Affected by CES1 Genetic Variation

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

  • Drug Metab Dispos. 2016 Apr;44(4):554-9. doi: 10.1124/dmd.115.068536.
Jian Shi 1,  Xinwen Wang 1,  Jenny Nguyen 1,  Audrey H Wu 1,  Barry E Bleske 1,  Hao-Jie Zhu 2
Affiliations

Affiliations

  • 1 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.).
  • 2 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.) [email protected].
PMID: 26817948 DOI: 10.1124/dmd.115.068536
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.

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