CES1 variants as determinant of ACE inhibitor activation: a healthy volunteer study

 描述（由申请方提供）：血管紧张素转换酶抑制剂（ACEIs）是全球最常用的处方药之一，常用于慢性肾脏病（CKD）患者治疗高血压、心力衰竭和减缓肾病进展。然而，ACEI治疗的结果在个体之间差异很大，并且在接受ACEI的患者中通常记录治疗失败和显著的副作用。ACEI治疗个体间差异的潜在机制目前仍不确定。目前迫切需要确定影响ACEI治疗结果的因素，以提高ACEI药物治疗的疗效和安全性。值得注意的是，大多数ACEI被合成为酯化的前药，以改善活性分子的口服生物利用度。ACEI前药的活化主要通过母体药物的代谢脱酯化作用发生在肝脏中。这一关键的激活步骤对于提供成功的治疗至关重要 结果。我们的小组和其他人已经证明，肝羧酸酯酶1（CES1）是负责激活ACEI前药在人类。已记录了CES1表达和活性的显著个体间变异性，这导致作为CES1底物的药物的代谢、治疗功效和耐受性不同。CES1的遗传变异越来越被认为是导致CES1功能变异的主要因素。我们已经发现了第一个临床上重要的CES1变体G143E，并证明G143E是一个功能丧失的变体，在体外激活ACEI前药。在这个建议中，我们将测试CES1遗传变异是一个假设， 影响ACEI前药的活化和随后的药代动力学和药效学的最重要的决定因素。具体目的是进行一项健康志愿者研究，以确定CES1 G143 E对依那普利（一种由CES1激活的ACEI前药模型）的激活和药理学活性的影响。在这个项目完成后，我们将建立一个关键作用的CES1变异体的药代动力学和药效学的ACEI前体药物。从这个探索性项目中产生的数据将形成一个全面的CES1药物遗传学研究的基础，以阐明CES1变体的功能，并确定这些变体对AECI前药治疗结果的影响。我们的长期目标是通过临床实施CES1药物遗传学来优化ACEI药物治疗。该项目还具有改善由CES1代谢的许多其他药物的治疗效果和安全性的巨大潜力。

 DESCRIPTION (provided by applicant): Angiotensin-converting enzyme inhibitors (ACEIs) are among the most commonly prescribed medications worldwide, and are frequently used in patients with chronic kidney disease (CKD) for the treatment of hypertension, heart failure, and deceleration of the progression of nephropathy. However, the outcome of ACEI treatment varies significantly between individuals, and therapeutic failure and significant side effects are commonly documented in patients receiving ACEIs. The underlying mechanisms of inter individual variability in response to ACEI therapy currently remain inconclusive. There is a critical need to identify the factors affecting therapeutic outcomes of ACEIs in order to improve efficacy and safety of ACEI pharmacotherapy. Of note, the majority of ACEIs are synthesized as esterified pro-drugs in order to improve otherwise poor oral bioavailability of the active molecule The activation of ACEI pro-drugs primarily occurs in the liver via metabolic de-esterification of the parent drugs. This critical activation step is essential in delivering a successful therapeutic outcome. Our group and others have demonstrated that hepatic carboxylesterase 1 (CES1) is responsible for the activation of ACEI pro-drugs in humans. Marked inter-individual variability in CES1 expression and activity has been documented, which results in varied metabolisms, therapeutic efficacy, and tolerability of drugs serving as the substrates of CES1. Genetic variation of CES1 is increasingly recognized as the major factor contributing to variability in CES1 function. We have discovered the first clinically important CES1 variants G143E, and demonstrated that the G143E is a loss-of-function variant with regard to activating ACEI pro-drugs in vitro. In this proposal, we will test the hypothesis that CES1 genetic variation is one of the foremost determinants influencing the activation and subsequent pharmacokinetics and pharmacodynamics of ACEI pro-drugs. The Specific Aim is to conduct a healthy volunteer study to determine the impact of the CES1 G143E on the activation and pharmacological activity of enalapril, a model ACEI pro-drug activated by CES1. At the completion of this project, we would have established a critical role of CES1 variants in the pharmacokinetics and pharmacodynamics of ACEI pro-drugs. The data generated from this exploratory project will form the foundation from which a comprehensive CES1 pharmacogenetic study can be launched to elucidate the function of CES1 variants and determine the impact of those variants on therapeutic outcomes of AECI pro-drugs. Our long-term goal is to optimize ACEI pharmacotherapy via clinical implementation of CES1 pharmacogenetics. This project also has a great potential for the improvement of therapeutic efficacy and safety of many other medications metabolized by CES1.