Inhibition of Carboxylesterase Metabolism by Ethanol

描述（由申请人提供）：羧酸酯酶在许多临床使用的药物的代谢和处置中起重要作用，包括血管紧张素转换酶抑制剂、抗癌剂、他汀类药物、中枢神经系统兴奋剂和滥用药物，如可卡因和海洛因。人类主要的羧酸酯酶hCE1和hCE2分别在肝脏和肠道中高度表达，它们在肝脏和肠道中参与两个对药物代谢至关重要的反应——将酯前药转化为活性代谢物和将活性药物水解为无活性部分。因此，抑制羧酸酯酶的催化活性可以显著改变底物药物的处置、治疗效果和毒性。包括抑制细胞色素P450酶的药物相互作用是众所周知的药物不良事件的原因。与此形成鲜明对比的是，关于药物相互作用对羧酸酯酶底物药物是否重要的信息很少。最近来自动物模型的证据表明，乙醇是羧酸酯酶介导的首过药物代谢的有效抑制剂，但这种相互作用的机制及其对人类的适用性仍然存在重要问题。我们的长期目标是表征体内影响羧酸酯酶底物药物处置和反应的因素。本应用程序的目标是将动物的发现转化为人类，并表征这种相互作用的体内机制。总体假设是乙醇通过抑制hCE1和hCE2来降低口服羧酸酯酶底物药物的首过代谢。为了验证这一假设，将在开放标签、随机、交叉设计的情况下，对健康的人类志愿者使用每种酶的特异性探针药物与乙醇或不含乙醇。具体目的是：1)确定乙醇对hCE1底物药物奥司他韦药代动力学的影响；2)测定乙醇对hCE2底物药物阿司匹林药动学的影响。美国有超过1亿人在消费乙醇，越来越多的药物依赖于羧酸酯酶的水解，认识到这些酶是药物相互作用代谢抑制的潜在靶点，有可能提高这类广泛处方药物的安全性和有效性。

DESCRIPTION (provided by applicant): Carboxylesterases play an important role in the metabolism and disposition of many clinically used medications including angiotensin-converting enzyme inhibitors, anticancer agents, statins, central nervous system stimulants, and drugs of abuse such as cocaine and heroin. The major human carboxylesterases, hCE1 and hCE2, are highly expressed in the liver and intestine, respectively, where they participate in two reactions important for drug metabolism - the conversion of ester prodrugs to active metabolites and the hydrolysis of active drugs to inactive moieties. Therefore, inhibition of the catalytic activity of carboxylesterases could significantly alter the disposition, therapeutic efficacy, and toxicity of substrate drugs. Drug interactions involving inhibition of cytochrome P450 enzymes are well known causes of adverse drug events. In distinct contrast, little information is available on whether drug interactions are important for carboxylesterase substrate drugs. Recent evidence from an animal model suggests that ethanol is a potent inhibitor of carboxylesterase- mediated first-pass drug metabolism, but important questions remain about the mechanisms of this interaction and the applicability to humans. Our long-term goal is to characterize in vivo factors affecting the disposition and response to carboxylesterase substrate drugs. The goal of this application is to translate the findings in animals to humans and characterize the in vivo mechanisms of this interaction. The overall hypothesis is that ethanol reduces first-pass metabolism of oral carboxylesterase-substrate drugs by inhibiting both hCE1 and hCE2. To test this hypothesis, probe drugs specific for each enzyme will be administered with and without ethanol to healthy human volunteers in an open label, randomized, crossover design. The specific aims are to: 1) determine the effects of ethanol on the pharmacokinetics of the hCE1 substrate drug oseltamivir; and 2) determine the effects of ethanol on the pharmacokinetics of the hCE2 substrate drug aspirin. With over 100 million people in the United States consuming ethanol and the growing number of drugs dependent on hydrolysis by carboxylesterases, recognition of these enzymes as potential targets for metabolic inhibition by drug interactions has the potential to improve the safe and effective use of this widely prescribed class of medications. PUBLIC HEALTH RELEVANCE: The inhibition of the carboxylesterase enzymes by ethanol could alter the effectiveness of many important drugs. Understanding this interaction is a necessary component for the safe and effective use of drugs metabolized by carboxylesterases. !