Carboxylesterase inhibitors from clinically available medicines and their impact on drug metabolism
Carboxylesterase inhibitors from clinically available medicines and their impact on drug metabolism
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临床可用药物中的羧酸酯酶抑制剂及其对药物代谢的影响
DOI：
10.1016/j.cbi.2021.109566
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发表时间：
2021-06-30
影响因子：
5.1
通讯作者：
Ge, Guang-Bo
中科院分区：
文献类型：
--
作者：
Song, Yun-Qing;Jin, Qiang;Ge, Guang-Bo
哺乳动物羧酸酯酶 (CES) 是丝氨酸水解酶超家族的关键成员，可水解多种带有酯或酰胺键的内源性物质和外源物质。在人类中，大多数已识别的 CES 被分为 CES1A 和 CES2A 亚科。对人类 CES（包括 hCES1A 和 hCES2A）的强抑制可能会调节 CES 底物药物的药代动力学特征，从而改变这些药物的药理学和毒理学反应。本综述涵盖了从临床可用药物中发现 hCES 抑制剂的最新进展，以及它们对 CES 相关药物代谢的影响。总结了来自临床可用药物（包括治疗药物、药物赋形剂和草药）的三个 hCES 抑制剂的综合清单，以及它们的抑制潜力和抑制参数。此外，还强调了 hCES 抑制剂引发药物/草药-药物相互作用 (DDI/HDI) 的潜在风险以及该领域的未来担忧。有效的 hCES 抑制剂可能会触发临床相关的 DDI/HDI，特别是当这些抑制剂与治疗窗非常窄的 CES 底物药物共同给药时。这里提供的所有数据和知识为临床医生评估临床可用的 hCES 抑制剂对药物代谢的风险提供了关键信息。未来，应该开发更实用和高度特异性的 hCES1A/hCES2A 底物，并用于 CES 介导的 DDI/HDI 的体外和体内研究。
Mammalian carboxylesterases (CES), the key members of the serine hydrolase superfamily, hydrolyze a wide range of endogenous substances and xenobiotics bearing ester or amide bond(s). In humans, most of identified CES are segregated into the CES1A and CES2A subfamilies. Strong inhibition on human CES (including hCES1A and hCES2A) may modulate pharmacokinetic profiles of CES-substrate drugs, thereby changing the pharmacological and toxicological responses of these drugs. This review covered recent advances in discovery of hCES inhibitors from clinically available medications, as well as their impact on CES-associated drug metabolism. Three comprehensive lists of hCES inhibitors deriving from clinically available medications including therapeutic drugs, pharmaceutical excipients and herbal medicines, alongside with their inhibition potentials and inhibition parameters, are summarized. Furthermore, the potential risks of hCES inhibitors to trigger drug/herb-drug interactions (DDIs/HDIs) and future concerns in this field are highlighted. Potent hCES inhibitors may trigger clinically relevant DDIs/HDIs, especially when these inhibitors are co-administrated with CES substrate-drugs with very narrow therapeutic windows. All data and knowledge presented here provide key information for the clinicians to assess the risks of clinically available hCES inhibitors on drug metabolism. In future, more practical and highly specific substrates for hCES1A/hCES2A should be developed and used for studies on CESmediated DDIs/HDIs both in vitro and in vivo.