摘要
清除率反映药物分子在体循环中被提取和消除的快慢程度。通过化学结构修饰方法降低化合物的清除率有助于改善化合物在体内的药代动力学和药效学性质。本文介绍了清除率的概念和研究意义,体内清除率的常见预测方法,重点综述了改善清除率的先导化合物结构优化策略,主要包括:通过降低亲脂性、封闭代谢位点、骨架修饰、增加位阻等方法降低肝脏代谢转化清除率;通过提高亲脂性、降低极性表面积、生物电子等排等方法降低胆汁排泄清除率或肾脏排泄清除率;最后总结了药物分子立体构型对清除率的影响。
Clearance reflects the speed of extraction and elimination of drug molecules from systemic circulation. Reducing the clearance of compounds using structure modification strategy could lead to good pharmacokinetic and pharmacodynamic properties. Herein, the concept of clearance, as well as several prediction methods of in vivo clearance are introduced. The strategies of reducing drug clearance are reviewed. These methods include reducing hepatic metabolic clearance through reducing lipophilicity, blocking metabolic site, scaffold modification and increasing steric hindrance;reducing biliary or renal excretion clearance through increasing lipophilicity, reducing polar surface area and bioisosterism. In addition, the influence of spatial configuration on drug clearance is also summarized.
作者
张蕊
王江
朱浩然
柳红
ZHANG Rui;WANG Jiang;ZHU Hao-ran;LIU Hong(State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China)
出处
《药学学报》
CAS
CSCD
北大核心
2021年第11期3030-3046,共17页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(21632008)。
关键词
清除率
肝脏代谢
排泄
亲脂性
立体构型
clearance
hepatic metabolism
excretion
lipophilicity
chiral configuration