Genetic determinants of ACEI prodrug activation

 说明(申请人提供)血管紧张素转换酶抑制剂(ACEIs)是世界上最常用的治疗高血压、左心室收缩功能障碍、急性心肌梗死和预防高血压的药物之一。 糖尿病肾病的进展。然而，血管紧张素转换酶抑制剂治疗的结果在个体和特定人群之间有很大差异。在接受血管紧张素转换酶抑制剂治疗的患者中，通常记录有不理想的反应、治疗失败和显著的副作用。在美国可供使用的ACEI中，大约80%是作为酯化前药合成的，以改善活性分子本来就很差的口服生物利用度。 ACEI前体药物的激活主要发生在肝脏中，通过母体药物的代谢去酯化。关键的激活步骤对于提供成功的治疗结果是必不可少的，因为活性代谢物的效力大约是它们各自的母体化合物的10-1000倍。我们的团队和其他人已经证明，肝脏中含量最丰富的水解酶--羧酸酯酶1(CES1)负责激活人类体内的ACEI前体药物。CES1的表达和活性存在显著的个体间差异，这导致作为CES1底物的许多药物的治疗效果和耐受性不同。CES1的遗传变异被认为是导致CES1功能变异的一个主要因素。我们是第一批证明某些CES1单核苷酸多态(SNPs)，如G143E，是功能丧失的变种之一，它可以显著影响CES1代谢的药物的药代动力学(PK)和药效学(PD)。在这个建议中，我们将检验CES1基因变异导致CES1功能个体间变异的假设， 是影响ACEI前体药活性和后续药理活性的决定因素之一。具体目的1是进行一项多剂量健康志愿者研究，以评估CES1基因变异对由CES1激活的模型ACEI前药依那普利的激活、PK和PD的影响。具体目标2是使用几种互补的体外方法来鉴定和表征影响CES1活性和表达的功能编码和调控CES1变体。这些既定目标的实现将是朝着建立一个证据基础迈出的重要一步，从而使血管紧张素转换酶抑制剂前体药物的使用更加个体化。该项目对于提高CES1代谢(激活或失活)的许多其他药物的疗效和安全性也具有重要的潜力。

 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.