Carboxylesterase 1 Plasma Biomarker for Precision Pharmacotherapy

摘要 羧酸酯酶1(CES1)是肝脏中的主要水解酶，在肝脏中有80-95%的水解酶活性。 人的肝脏。CES1负责许多临床上重要药物的代谢，环境 毒素和内源性物质。CES1的肝脏表达和活性在不同的人之间存在显著差异 个体，这是造成药物反应个体间差异的主要因素 由CES1代谢。我们发现了一个功能缺失的CES1非同义变异体G143E (Rs71647871)，并证明该变异可显著影响药代动力学(PK)和 CES1底物药物的药效学研究。但是，G143E变体不会影响CES1 由于其频率较低，因此只对CES1功能的一小部分变异有贡献。 因此，迫切需要能够预测CES1表达的生物标志物来提高 CES1代谢的多种药物的有效性和安全性。我们的初步研究表明，血浆 CES1蛋白浓度可以预测CES1在体内的功能。本提案的目标1是评估 血浆CES1蛋白与选择性CES1底物依那普利的PK和PD的相关性 从正在进行的依那普利PK研究(NCT03051282)收集的血浆样本。依那普利PK研究 最初设计用于确定CES1变异体G143E对健康人群中依那普利PK和PD的影响 研究对象。我们预计，将血浆CES1蛋白生物标记物和CES1遗传生物标记物结合起来将 解释在依那普利的PK和PD中观察到的大部分变异性。目标2是确定两者之间的相关性 配对血浆和肝脏CES1蛋白浓度与肝脏CES1蛋白水平的关系 纸巾。这项研究将提供机制证据，支持血浆CES1蛋白浓度 预测肝脏中CES1蛋白水平。我们预计拟议的项目将建立血浆CES1 蛋白质作为预测CES1底物药物PK和PD的可靠生物标志物。该项目具有很高的 由于许多CES1底物药物的治疗指标较窄，而血浆CES1蛋白 生物标记物引导的精确给药可以显著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例 CES1蛋白作为优化治疗方案的生物标志物。这项研究也将对未来有所启示。 其他肝脏药物代谢酶的血浆蛋白生物标志物的研究。

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.