Carboxylesterase 1 Plasma Biomarker for Precision Pharmacotherapy

用于精准药物治疗的羧酸酯酶 1 血浆生物标志物

• 批准号: 10686242
• 负责人: Haojie Zhu
• 金额: $ 31.2万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686242
• 关键词: Affect; Area; Biological Assay; Biological Markers; Biopsy; Carboxylesterase 1; Catechol O-Methyltransferase; Clinical; Code; Data; Distant; Dose; Drug Kinetics; Effectiveness; Enalapril; Enzymes; Exhibits; Exposure to; Frequencies; Gene Frequency; Genes; Genetic Markers; Hepatic; Human; Hydrolase; Individual; Literature; Liver; Lung; Measures; Metabolism; Minor; Nucleic Acid Regulatory Sequences; Outcome; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Plasma; Plasma Proteins; Proteins; Proteomics; Publishing; Regimen; Reporting; Ritalin; Safety; Sampling; Therapeutic; Therapeutic Agents; Therapeutic Index; Time; Tissues; Toxic Environmental Substances; Variant; aldehyde dehydrogenases; clinically significant; design; drug metabolism; genetic variant; improved; in vivo; individual patient; inter-individual variation; loss of function; medication safety; pharmacokinetics and pharmacodynamics; potential biomarker; predictive marker; protein biomarkers; protein expression; response; sulfotransferase; therapy outcome

Abstract Carboxylesterase 1 (CES1) is the primary hepatic hydrolase, contributing to 80-95% hydrolytic activity in the human liver. CES1 is responsible for the metabolism of many clinically important medication, environmental toxins, and endogenous substances. Hepatic expression and activity of CES1 vary markedly among individuals, which is a major factor contributing to the interindividual variability in response to medications metabolized by CES1. We have identified a loss-of-function CES1 nonsynonymous variant, G143E (rs71647871), and demonstrated that this variant could significantly affect the pharmacokinetics (PK) and pharmacodynamics (PD) of CES1 substrate drugs. However, the G143E variant does not affect CES1 expression and only contributes to a small portion of CES1 function variability because of its low frequency. Therefore, biomarkers capable of predicting CES1 expression are urgently needed to improve the effectiveness and safety of numerous drugs metabolized by CES1. Our preliminary study showed that plasma CES1 protein concentrations were predictive of CES1 in vivo function. Aim 1 of this proposal is to evaluate the correlations between plasma CES1 protein and the PK and PD of the selective CES1 substrate enalapril using the plasma samples collected from an ongoing enalapril PK study (NCT03051282). This enalapril PK study was originally designed to determine the effect of the CES1 variant G143E on enalapril PK and PD in healthy subjects. We expect that combining the plasma CES1 protein biomarker and the CES1 genetic biomarker will explain much of the variability observed in the PK and PD of enalapril. Aim 2 is to determine the correlation between CES1 protein plasma concentrations and hepatic CES1 protein levels in matched plasma and liver tissues. This study will provide mechanistic evidence to support that plasma CES1 protein concentrations are predictive of CES1 protein levels in the liver. We expect that the proposed project will establish plasma CES1 protein as a reliable biomarker for predicting the PK and PD of CES1 substrate drugs. The project is highly impactful because many CES1 substrate drugs have narrow therapeutic indexes, and plasma CES1 protein biomarker-guided precision dosing could significantly improve the efficacy and safety of these medications. The project has the potential to change the paradigm of how to treat patients more effectively by using plasma CES1 protein as a biomarker to optimize therapeutic regimens. This study will also shed light on future research on plasma protein biomarkers for other hepatic drug-metabolizing enzymes.

摘要 羧酸酯酶1（CES 1）是主要的肝水解酶，在肝脏中贡献80-95%的水解活性。 人类肝脏CES 1负责许多临床上重要的药物代谢、环境代谢和代谢。 毒素和内源性物质。肝组织中CES 1的表达和活性在不同的 这是导致个体间对药物反应差异的主要因素 由CES 1代谢。我们已经确定了一个功能丧失的CES 1非同义变体，G143 E （rs71647871），并证明该变体可显著影响药代动力学（PK）和 CES 1底物药物的药效学（PD）。然而，G143 E变体不影响CES 1， CES 1基因表达水平较低，由于其频率较低，仅对CES 1功能变异性的一小部分有贡献。 因此，迫切需要能够预测CES 1表达的生物标志物来改善CES 1表达。 有效性和安全性的许多药物代谢的CES 1。我们的初步研究表明血浆 CES 1蛋白浓度可预测CES 1的体内功能。本提案的目标1是评估 血浆CES 1蛋白与选择性CES 1底物依那普利的PK和PD之间的相关性， 从正在进行的依那普利PK研究（NCT 03051282）中采集的血浆样本。本依那普利PK研究 最初设计用于确定CES 1变体G143 E对健康受试者中依那普利PK和PD的影响。 科目我们期望将血浆CES 1蛋白质生物标志物和CES 1遗传生物标志物结合起来， 解释了依那普利PK和PD中观察到的变异性。目标2：确定相关性 在匹配的血浆和肝脏中，CES 1蛋白血浆浓度与肝脏CES 1蛋白水平之间 组织中这项研究将提供机制证据，支持血浆CES 1蛋白浓度是 预测肝脏中的CES 1蛋白水平。我们预计，拟议的项目将建立血浆CES 1 蛋白作为预测CES 1底物药物PK和PD的可靠生物标志物。该项目高度 因为许多CES 1底物药物具有狭窄的治疗指数，并且血浆CES 1蛋白 生物标志物指导的精确给药可以显着提高这些药物的疗效和安全性。 该项目有可能改变如何通过使用血浆更有效地治疗患者的范式 CES 1蛋白作为生物标志物优化治疗方案。这项研究也将揭示未来 其他肝脏药物代谢酶的血浆蛋白生物标志物研究。