The role of human carboxylesterases in drug metabolism: have we overlooked their importance?
The role of human carboxylesterases in drug metabolism: have we overlooked their importance?
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DOI：
10.1002/phar.1194
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发表时间：
2013-02
期刊：
影响因子：
4.1
通讯作者：
Parker RB
中科院分区：
文献类型：
--
作者：
Laizure SC;Herring V;Hu Z;Witbrodt K;Parker RB
羧酸酯酶是广泛分布于哺乳动物体内的多基因酶家族，其催化酯、酰胺、硫酯和氨基甲酸酯的水解。在人类中，两种羧酸酯酶hCE 1和hCE 2是药物代谢的重要途径。两者都在肝脏中表达，但hCE 1的水平大大超过hCE 2。在肠道中，只有高水平的hCE 2表达。最常见的药物底物是专门设计用于增强口服生物利用度的酯前药，其在从胃肠道吸收后必须通过水解水解而水解成其活性羧酸。然而，羧酸酯酶在某些药物水解为无活性代谢物的过程中也起着重要作用。它已被广泛接受的药物进行水解hCE 1和hCE 2是不受临床显着的改变，在他们的处置，但现在有一个显着的和越来越多的证据表明，遗传多态性，药物相互作用，药物-疾病相互作用和其他因素是重要的决定因素，在治疗反应的变异性羧酸酯酶底物药物。药物治疗的安全性和有效性的意义是深远的，因为患者暴露于底物药物包括来自广泛处方的治疗类别的许多药物，如血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂、抗血小板药、HMG-CoA抑制剂、抗病毒药和中枢神经系统药物。
Carboxylesterases are a multi-gene family of enzymes widely distributed throughout the body of mammals that catalyze the hydrolysis of esters, amides, thioesters, and carbamates. In humans, two carboxylesterases, hCE1 and hCE2, are important pathways of drug metabolism. Both are expressed in the liver, but levels of hCE1 greatly exceed those of hCE2. In the intestine only high levels of hCE2 are expressed. The most common drug substrates are ester prodrugs specifically designed to enhance oral bioavailability that must be hydrolyzed to their active carboxylic acid by hydrolysis after absorption from the gastrointestinal tract. However, carboxylesterases also play an important role in the hydrolysis of some drugs to inactive metabolites. It has been widely accepted that drugs undergoing hydrolysis by hCE1 and hCE2 are not subject to clinically significant alterations in their disposition, but there is now a significant and growing body of evidence that genetic polymorphisms, drug-drug interactions, drug-disease interactions and other factors are important determinants of the variability in the therapeutic response to carboxylesterase-substrate drugs. The implications for the safe and effective use of drug therapy is far-reaching, as the patient exposure to substrate drugs includes numerous agents from widely prescribed therapeutic classes such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, antiplatelets, HMG-CoA inhibitors, antivirals, and central nervous system agents.