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Genetic determinants of ACEI prodrug activation

Genetic determinants of ACEI prodrug activation
ACEI 前药激活的遗传决定因素
批准号:
9883031
负责人:
Haojie Zhu
金额:
$38.7万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-02-15 至 2021-01-31

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项目成果

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中文摘要
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英文摘要
 DESCRIPTION (provided by applicant) Angiotensin-converting enzyme inhibitors (ACEIs) are among the most frequently prescribed medications worldwide for the treatment of essential hypertension, left ventricular systolic dysfunction, acute myocardial infarction, and prevention of the progression of diabetic nephropathy. However, the outcome of ACEI treatment varies significantly between individuals and selected populations. Suboptimal response, therapeutic failure, and significant side effects are commonly documented in patients receiving ACEI therapy. Approximately 80% of the ACEIs available for use in the US are synthesized as esterified prodrugs in order to improve otherwise poor oral bioavailability of the active molecule. The activation of ACEI prodrugs primarily occurs in the liver via metabolic de-esterification of th parent drug. The critical activation step is essential in delivering a successful therapeutic outcome since the active metabolites are approximately 10-1000 times more potent relative to their respective parent compounds. Our group and others have demonstrated that carboxylesterase 1 (CES1), the most abundant hydrolase in the liver, is responsible for the activation of ACEI prodrugs in humans. Marked interindividual variability in CES1 expression and activity has been documented, which results in varied therapeutic efficacy and tolerability of many drugs serving as substrates of CES1. Genetic variation of CES1 is considered to be a major factor contributing to variability in CES1 function. We are among the first demonstrating that some CES1 single nucleotide polymorphisms (SNPs), such as the G143E, are loss-of- function variants, which can significantly affect both pharmacokinetics (PK) and pharmacodynamics (PD) of medications metabolized by CES1. In this proposal, we will test the hypothesis that CES1 genetic variation contributes to interindividual variability of CES1 function, and is one of the determinants influencing the activation and subsequent pharmacological activity of ACEI prodrugs. Specific Aim 1 is to conduct a multiple- dose healthy volunteer study to evaluate the impact of CES1 genetic variation on the activation, PK, and PD of enalapril, a model ACEI prodrug activated by CES1. Specific Aim 2 is to identify and characterize functional coding and regulatory CES1 variants that affect the activity and expression of CES1 using several complementary in vitro approaches. The achievement of these stated aims will represent a major step towards the establishment of an evidence base from which a more individualized use of ACEI prodrugs can emerge. This project also has significant potential for the improvement of therapeutic efficacy and safety of many other medications metabolized (activated or deactivated) by CES1.
期刊论文(9)
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科研奖励(0)
会议论文
DOI: 10.3390/pharmaceutics13101656
发表时间: 2021-10-11
期刊: Pharmaceutics
影响因子: 5.4
作者: [Li J, Liu S, Shi J, Zhu HJ]
通讯作者: Zhu HJ
Comparison of protein expression between human livers and the hepatic cell lines HepG2, Hep3B, and Huh7 using SWATH and MRM-HR proteomics: Focusing on drug-metabolizing enzymes.
使用 SWATH 和 MRM-HR 蛋白质组学比较人肝脏与肝细胞系 HepG2、Hep3B 和 Huh7 之间的蛋白质表达:关注药物代谢酶。
DOI: 10.1016/j.dmpk.2018.03.003
发表时间: 2018-04
期刊: Drug metabolism and pharmacokinetics
影响因子: 2.1
作者: [Shi J, Wang X, Lyu L, Jiang H, Zhu HJ]
通讯作者: Zhu HJ
DOI: 10.1111/cts.12989
发表时间: 2021-07
期刊: Clinical and translational science
影响因子: --
作者: [Wang X, Her L, Xiao J, Shi J, Wu AH, Bleske BE, Zhu HJ]
通讯作者: Zhu HJ
A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms.
羧酸酯酶 1 非同义多态性的综合功能评估。
DOI: 10.1124/dmd.117.077669
发表时间: 2017
期刊: Drug metabolism and disposition: the biological fate of chemicals
影响因子: --
作者: [Wang,Xinwen, Rida,Nada, Shi,Jian, Wu,AudreyH, Bleske,BarryE, Zhu,Hao-Jie]
通讯作者: Zhu,Hao-Jie
6
    Carboxylesterase 1 Plasma Biomarker for Precision Pharmacotherapy
    Modifying Remdesivir Prodrug Design to Enhance the Active Metabolite Accumulation in the Lung (Resubmission)
    Modifying Remdesivir Prodrug Design to Enhance the Active Metabolite Accumulation in the Lung (Resubmission)
    CES1 variants as determinant of ACE inhibitor activation: a healthy volunteer study
    海外基金