Beaumont Kevin, Gardner Iain, Chapman Kathryn, Hall Michael, Rowland Malcolm
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK.
J Pharm Sci. 2011 Oct;100(10):4518-35. doi: 10.1002/jps.22635. Epub 2011 Jun 24.
Prediction of human clearance plays a critical role in early drug discovery and development. However, there is no consensus on the most appropriate method to gather such data. A variety of in vivo and in vitro methods exist and a comparison of in vitro data from a standard set of compounds has been called for. This paper compares the predictive capacity of human liver microsomes and single-species scaling (SSS) from rat and non-human primate for a standard set of compounds representing marketed drugs. The results enable a framework to be proposed wherein compounds are selected using in vitro methods alone or in vitro methods combined with SSS in the rat. Further investigation of this framework has the potential to increase the efficiency of drug discovery and reduce animal use.
人体清除率的预测在药物早期发现和开发中起着关键作用。然而，对于收集此类数据的最合适方法尚无共识。存在多种体内和体外方法，有人呼吁对一组标准化合物的体外数据进行比较。本文比较了人肝微粒体以及大鼠和非人类灵长类动物的单物种标度法（SSS）对一组代表上市药物的标准化合物的预测能力。研究结果有助于提出一个框架，即仅使用体外方法或体外方法与大鼠的SSS相结合来选择化合物。对该框架的进一步研究有可能提高药物发现的效率并减少动物使用。
