An Guohua
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA.
J Clin Pharmacol. 2017 Feb;57(2):137-150. doi: 10.1002/jcph.804. Epub 2016 Sep 6.
Nonlinearities are commonplace in pharmacokinetics, and 1 special source is the saturable binding of the drug to a high-affinity, low-capacity target, a phenomenon known as target-mediated drug disposition (TMDD). Compared with large-molecule compounds undergoing TMDD, which has been well recognized due to its high prevalence, TMDD in small-molecule compounds is more counterintuitive and has not been well appreciated. With more and more potent small-molecule drugs acting on highly specific targets being developed as well as increasingly sensitive analytical techniques becoming available, many small-molecule compounds have recently been reported to have nonlinear pharmacokinetics imparted by TMDD. To expand our current knowledge of TMDD in small-molecule compounds and increase the awareness of this clinically important phenomenon, this minireview provides an overview of the small-molecule compounds that demonstrate nonlinear pharmacokinetics imparted by TMDD. The present review also summarizes the general features of TMDD in small-molecule compounds and highlights the differences between TMDD in small-molecule compounds and large-molecule compounds.
非线性现象在药代动力学中很常见，其中一个特殊来源是药物与高亲和力、低容量靶点的饱和性结合，这种现象称为靶点介导的药物处置（TMDD）。与因高发生率而得到充分认识的大分子化合物的TMDD相比，小分子化合物中的TMDD更具反直觉性，尚未得到充分认识。随着越来越多作用于高度特异性靶点的强效小分子药物的开发以及越来越灵敏的分析技术的出现，最近有许多小分子化合物被报道具有由TMDD导致的非线性药代动力学。为了扩展我们目前对小分子化合物中TMDD的认识，并提高对这一临床重要现象的认识，本综述概述了表现出由TMDD导致的非线性药代动力学的小分子化合物。本综述还总结了小分子化合物中TMDD的一般特征，并强调了小分子化合物与大分子化合物中TMDD的差异。
