Metabolite Identification in the Preclinical and Clinical Phase of Drug Development.

IF 1.8 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current drug metabolism Pub Date : 2021-01-01 DOI:10.2174/1389200222666211006104502

Yali Wu, Lulu Pan, Zhendong Chen, Yuandong Zheng, Xingxing Diao, Dafang Zhong

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引用次数: 12

Abstract

Metabolite identification plays a critical role in the phases during drug development. Drug metabolites can contribute to efficacy, toxicity, and drug-drug interaction. Thus, the correct identification of metabolites is essential to understand the behavior of drugs in humans. Drug administration authorities (e.g., FDA, EMA, and NMPA) emphasize evaluating the safety of human metabolites with exposure higher than 10% of the total drugrelated components. Many previous reviews have summarized the various methods, tools, and strategies for the appropriate and comprehensive identification of metabolites. In this review, we focus on summarizing the importance of identifying metabolites in the preclinical and clinical phases of drug development. Summarized scenarios include the role of metabolites in pharmacokinetics/pharmacodynamics (PK/PD) analysis, disproportional exposure of metabolites that contribute to drug toxicity, changes in metabolite exposure in renal-impaired patients, covalent tyrosine kinase inhibitors (anticancer drugs), and metabolite identification of drug candidates from natural medicines. This review is aimed to provide meaningful insight into the significant role of metabolite identification in drug development.

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药物开发临床前和临床阶段的代谢物鉴定。

代谢物鉴定在药物开发的各个阶段起着至关重要的作用。药物代谢物可以促进疗效、毒性和药物-药物相互作用。因此，正确识别代谢物对于理解药物在人体内的行为至关重要。药品监督管理部门(如FDA、EMA和NMPA)强调评估暴露量高于总药物相关成分10%的人体代谢物的安全性。许多先前的综述总结了各种方法、工具和策略，以适当和全面地鉴定代谢物。在这篇综述中，我们重点总结了在药物开发的临床前和临床阶段鉴定代谢物的重要性。总结的场景包括代谢物在药代动力学/药效学(PK/PD)分析中的作用，代谢物对药物毒性的不成比例暴露，肾脏受损患者代谢物暴露的变化，共价酪氨酸激酶抑制剂(抗癌药物)，以及天然药物候选药物的代谢物鉴定。本综述旨在为代谢物鉴定在药物开发中的重要作用提供有意义的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current drug metabolism 医学-生化与分子生物学

CiteScore

4.30

自引率

4.30%

发文量

审稿时长

4-8 weeks

期刊介绍： Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism. More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.