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

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 wildtype 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.

Assessment of Drug–Drug Interaction Potential Between Atorvastatin and LCZ696, A Novel Angiotensin Receptor Neprilysin Inhibitor, in Healthy Chinese Male Subjects

“…LCZ696 is rapidly absorbed following oral administration, with peak plasma concentrations of sacubitril, LBQ657, and valsartan observed within a median time of 0.5-4.0 h [9]. Sacubitril is almost completely metabolized by hepatic carboxylesterase 1 (CES-1) but not CES-2, to the active metabolite LBQ657 [10]. This is reflected in minimal recovery of sacubitril in urine and feces (\3 %).…”

Effect of renal function on the pharmacokinetics of LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor

“…Sacubitril is an inactive prodrug and is rapidly hydrolyzed by carboxyl esterases (CES) to form sacubitrilat (also reported as LBQ657), the active neprilysin inhibitor. It was reported that CES-1 but not CES-2 is involved in this conversion, while the role of other CES polymorphs is unknown [2]. Simultaneous inhibition of neprilysin and angiotensin II type-1 (AT1) receptor with LCZ696 showed superior benefits over enalapril in reducing the CV deaths and HF hospitalizations (primary composite endpoint) in the PARADIGM-HF trial in patients with HFrEF [3].…”

Kidney Response to Heart Failure: Proteomic Analysis of Cardiorenal Syndrome

“…Carboxylesterase 1 is a serine esterase, responsible for the hydrolysis of ester-and amide-bond-containing substrates, including xenobiotics and drugs. Most of ACE inhibitors and sacubitril are ester pro-drugs that are hydrolyzed to their active metabolites just by CES1 [30]. Low CES1 activity-variant carriers may have worse therapeutic response to ACE inhibitors [31].…”