Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients

Xiao, Fang; Liu, Min; Chen, Bilian; Cao, Shan; Liu, Zhao‐Qian; Zhou, Hong‐Hao; Zhang, Gan; Zhang, Wei

doi:10.1038/s41598-017-07736-1

Cited by 22 publications

(12 citation statements)

References 26 publications

(25 reference statements)

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“…The study also found that the S75N polymorphism was more frequent in patients with acute coronary syndrome (MAF 22%) than in the general population (MAF 5%). The authors concluded that there was a significant association between the S75N polymorphism and the outcome of clopidogrel therapy (Xiao et al, 2017). However, this result conflicts with another study that found the S75N variant to be not associated with the outcomes of patients treated with methylphenidate (Johnson et al, 2013).…”

Section: Pharmacogenetics Of Other Ces1 Genetic Variantsmentioning

confidence: 87%

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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Section: Pharmacogenetics Of Other Ces1 Genetic Variantsmentioning

confidence: 87%

Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators

Her

Zhu

2019

Drug Metab Dispos

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“…Клопидогрел представляет собой тиенопиридин, который превращается в фармакологически активный тиоловый метаболит через неактивный промежуточный 2-оксо-клопидогрел [5]. Реакция катализируется ферментами цитохрома P450, включая CYP2C19, CYP3A, CYP2B6, CYP1A2 и CYP2C9 [7]. Однако только 15% клопидогрела становится биодоступным [7].…”

Section: Discussionunclassified

“…Реакция катализируется ферментами цитохрома P450, включая CYP2C19, CYP3A, CYP2B6, CYP1A2 и CYP2C9 [7]. Однако только 15% клопидогрела становится биодоступным [7]. Активный метаболит 5-тиол клопидогрел ингибирует индуцированную АДФ активацию и агрегацию тромбоцитов путем необратимого связывания с рецептором P2Y 12 на поверхности клеток [8].…”

Section: Discussionunclassified

Влияние Полиморфизма Гена CES1 На Антиагрегантный Эффект Блокатора P2Y 12 Рецепторов Клопидогрела

Мирзаев¹,

Osipova²,

Kitaeva³

et al. 2018

Clin Pharmacol Ther

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“…CES1 polymorphism has also been investigated in recent years as a contributing factor to inter‐individual variability of clopidogrel activation and antiplatelet activity. A number of studies documented that the CES1 SNPs G143E (rs71647871) and D260fs16 (rs71647872) exhibited markedly decreased enzymatic activity in the hydrolysis of the CES1 substrates, and CES1A2 −816C as well as CES S75N were associated with attenuated platelet reactivity to clopidogrel . Association of P2Y12 and CES1 polymorphisms to clopidogrel resistance however remains to be verified and warrants further investigation.…”

Section: Cyp Genotype‐based Drug Therapiesmentioning

confidence: 99%

Cytochrome P450 genotype‐guided drug therapies: An update on current states

Dong

Tan

Pan

et al. 2018

Clin Exp Pharma Physio

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Over the past 2 decades, knowledge of the role and clinical value of pharmacogenetic markers has expanded so that individualized pre-emptive therapy based on genetic background of patients could be within reach for clinical implementation. This is evidenced from the frequent updating of drug labels that incorporates pharmacogenetic information (where compelling data become available) by the regulatory agencies (such as the US FDA), and the periodical publication of guidelines of specific therapeutic recommendations based on the results of pharmacogenetic tests by the pharmacogenetics working groups or consortiums of professional bodies. Clinical relevance of the cytochrome P450 (CYP) polymorphism related to dose, effectiveness and/or toxicity of key drugs are presented in this review, including that of warfarin, clopidogrel, tricyclic antidepressants, and proton pump inhibitors. Prospect for routine clinical application of CYP genotyping before prescribing drugs is still currently unclear due to challenges and barriers associated with availability of well-defined and validated pharmacogenetic studies, the interpretation, result reporting and potential error of genotype testing, involvement of non-genetic factors, and other patient's demographic and disease conditions. Further studies to provide additional supporting clinical data and acceleration of pharmacogenetic testing standards and techniques should help improve the evidence base needed for clinical utility and hence move the implementation of genotype-guided therapy in clinical practice a step closer to reality.

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Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients

Cited by 22 publications

References 26 publications

Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators

Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators

Влияние Полиморфизма Гена CES1 На Антиагрегантный Эффект Блокатора P2Y 12 Рецепторов Клопидогрела

Cytochrome P450 genotype‐guided drug therapies: An update on current states

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