Prognostic impact of carboxylesterase 1 gene variants in patients with congestive heart failure treated with angiotensin-converting enzyme inhibitors

Nelveg-Kristensen, Karl Emil; Madsen, Majbritt Busk; Torp‐Pedersen, Christian; Køber, Lars; Egfjord, Martin; Hansen, Torben Frøstrup; Pedersen, Oluf; Rasmussen, Henrik Berg; Hansen, Peter Riis

doi:10.1097/fpc.0000000000000203

Cited by 6 publications

(2 citation statements)

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“…In one such study, the variant was evaluated for its effect on the outcomes of ACEI prodrugs in patients with congestive heart failure (n 5 200) who underwent ACEI prodrug dose titrations. The study reported -75G.T did not significantly impact plasma angiotensin (AT) II/ATI ratios, and furthermore, the -75G.T variant was not significantly associated with fatal outcomes (i.e., cardiovascular death and all-cause death) (Nelveg- Kristensen et al, 2016). The study with isoniazid had similar results showing no significant association between the variant and isoniazid-induced hepatotoxicity (n 5 170) (Yamada et al, 2010).…”

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confidence: 86%

“…Suzaki et al (2013b) evaluated the relationship between CNVs of CES1 and oseltamivir PK parameters but did not find any correlation. Nelveg- Kristensen et al (2016) studied the relationship between CNV and ACEI prodrugs, and again, no association was found. Moreover, an in vitro study showed CES1 protein expression levels to be comparable among human livers with different copy numbers of functional CES1 gene (Wang et al, 2016b).…”

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confidence: 99%

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Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators

Her

Zhu

2019

Drug Metab Dispos

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Carboxylesterase (CES) 1 is the most abundant drug-metabolizing enzyme in human livers, comprising approximately 1% of the entire liver proteome. CES1 is responsible for 80%-95% of total hydrolytic activity in the liver and plays a crucial role in the metabolism of a wide range of drugs (especially ester-prodrugs), pesticides, environmental pollutants, and endogenous compounds. Expression and activity of CES1 vary markedly among individuals, which is a major contributing factor to interindividual variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by CES1. Both genetic and nongenetic factors contribute to CES1 variability. Here, we discuss genetic polymorphisms, including singlenucleotide polymorphisms (SNPs), and copy number variants and nongenetic contributors, such as developmental status, genders, and drug-drug interactions, that could influence CES1 functionality and the PK and PD of CES1 substrates. Currently, the loss-of-function SNP G143E (rs71647871) is the only clinically significant CES1 variant identified to date, and alcohol is the only potent CES1 inhibitor that could alter the therapeutic outcomes of CES1 substrate medications. However, G143E and alcohol can only explain a small portion of the interindividual variability in the CES1 function. A better understanding of the regulation of CES1 expression and activity and identification of biomarkers for CES1 function in vivo could lead to the development of a precision pharmacotherapy strategy to improve the efficacy and safety of many CES1 substrate drugs. SIGNIFICANCE STATEMENTThe clinical relevance of CES1 has been well demonstrated in various clinical trials. Genetic and nongenetic regulators can affect CES1 expression and activity, resulting in the alteration of the metabolism and clinical outcome of CES1 substrate drugs, such as methylphenidate and clopidogrel. Predicting the hepatic CES1 function can provide clinical guidance to optimize pharmacotherapy of numerous medications metabolized by CES1.

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confidence: 86%