4 The Maltings , Walmer , Kent CT14 7AR , U.K.
Pharmacokinetics, Dynamics and Metabolism , Pfizer Inc. , Cambridge , Massachusetts 02139 , United States.
J Med Chem. 2019 Mar 14;62(5):2245-2255. doi: 10.1021/acs.jmedchem.8b01263. Epub 2018 Oct 17.
Due to its implications for both dose level and frequency, clearance rate is one of the most important pharmacokinetic parameters to consider in the design of drug candidates. Clearance can be classified into three general categories, namely, metabolic transformation, renal excretion, and hepatobiliary excretion. Within each category, there are a host of biochemical and physiological mechanisms that ultimately determine the clearance rate. Physiochemical properties are often indicative of the rate-determining mechanism, with lipophilic molecules tending toward metabolism and hydrophilic, polar molecules tending toward passive or active excretion. Optimization of clearance requires recognition of the major clearance mechanisms and use of the most relevant in vitro and in vivo tools to develop structure-clearance relationships. The reliability of methods to detect and predict human clearance varies across mechanisms. While methods for metabolic and passive renal clearance have proven reasonably robust, there is a clear need for better tools to support the optimization of transporter-mediated clearance.
由于其对剂量水平和频率都有影响，清除率是药物候选物设计中需要考虑的最重要的药代动力学参数之一。清除率可以分为三大类，即代谢转化、肾排泄和肝胆排泄。在每种类别中，都有许多生化和生理机制最终决定了清除率。物理化学性质通常表明了限速机制，亲脂性分子倾向于代谢，而亲水性、极性分子则倾向于被动或主动排泄。清除率的优化需要认识到主要的清除机制，并使用最相关的体外和体内工具来建立结构-清除关系。检测和预测人体清除率的方法在不同机制下的可靠性有所不同。虽然代谢和被动肾清除的方法已经被证明相当可靠，但显然需要更好的工具来支持转运体介导的清除率的优化。
