Genetic determinants of ACEI prodrug activation

 描述（由申请人提供）血管紧张素转换酶抑制剂（ACEIs）是全世界最常用于治疗原发性高血压、左心室收缩功能障碍、急性心肌梗死和预防高血压的处方药之一。 糖尿病肾病的治疗然而，ACEI治疗的结果在个体和选定的人群之间差异很大。在接受ACEI治疗的患者中，通常记录了次优反应、治疗失败和显著的副作用。大约80%的可用于美国的ACEIs合成为酯化前药，以改善活性分子的口服生物利用度。 ACEI前药的活化主要发生在肝脏中，通过母体药物的代谢脱酯化作用。关键的活化步骤对于提供成功的治疗结果是必不可少的，因为活性代谢物相对于其各自的母体化合物的效力大约高10-1000倍。我们的研究小组和其他人已经证明，羧酸酯酶1（CES 1），在肝脏中最丰富的水解酶，是负责激活ACEI前药在人类。CES 1表达和活性的显著个体间差异已被记录，这导致作为CES 1底物的许多药物的治疗效果和耐受性不同。CES 1的遗传变异被认为是导致CES 1功能变异的主要因素。我们是第一个证明某些CES 1单核苷酸多态性（SNP），如G143 E，是功能丧失的变体，可以显著影响CES 1代谢的药物的药代动力学（PK）和药效学（PD）。在这项提议中，我们将检验CES 1遗传变异有助于CES 1功能个体间变异的假设， 并且是影响ACEI前药的活化和随后的药理学活性的决定因素之一。具体目的1是进行多次给药健康志愿者研究，以评价CES 1遗传变异对依那普利（一种由CES 1激活的ACEI前药模型）的激活、PK和PD的影响。具体目标2是使用几种互补的体外方法鉴定和表征影响CES 1活性和表达的功能编码和调节CES 1变体。这些目标的实现将是建立证据基础的重要一步，从证据基础中可以出现ACEI前药的更个性化的使用。该项目还具有显著的潜力，可以改善由CES 1代谢（激活或失活）的许多其他药物的治疗效果和安全性。

 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.