Smith D A, Jones B C, Walker D K
Department of Drug Metabolism, Pfizer Central Research, Sandwich, Kent, U.K.
Med Res Rev. 1996 May;16(3):243-66. doi: 10.1002/(SICI)1098-1128(199605)16:3<243::AID-MED2>3.0.CO;2-Z.
Drug metabolism input to the discovery process had historically been on an empirical case-by-case basis, since, detailed descriptors of the effect on pharmacokinetics of a change in structure or physicochemical property were not available. Considerable advances have been made in recent years, such that basic rules can be applied to predict the behavior of a compound in man based on physicochemistry and structure. This is particularly true in the areas of absorption, distribution, and clearance. In particular, knowledge of the reactions catalyzed by the enzymes of drug metabolism, including the cytochrome P450 super family, can be used in the design of new chemical entities, together with the usual pharmacological-derived SAR. The combination of both pharmacokinetics and pharmacodynamics at the discovery stage leads to drugs with optimum performance characteristics. Such drugs are easier to develop, representing a huge saving in resources. Moreover, the marketed compound is much more likely to find high clinical utilization. This review uses dofetilide, fluconazole, and amlodipine to highlight the multifaceted consequences of changing chemical structure, in terms of drug disposition, and reinforces these principles with examples from the literature.
在药物研发过程中，由于缺乏关于结构或物理化学性质变化对药代动力学影响的详细描述符，药物代谢方面的投入在历史上一直是基于经验逐个案例进行的。近年来取得了相当大的进展，以至于可以应用基本规则，根据物理化学和结构来预测化合物在人体内的行为。在吸收、分布和清除等方面尤其如此。特别是，包括细胞色素P450超家族在内的药物代谢酶催化的反应知识，可与通常的药理学衍生的构效关系一起用于新化学实体的设计。在发现阶段将药代动力学和药效学结合起来，会产生具有最佳性能特征的药物。这类药物更容易开发，可节省大量资源。此外，上市的化合物更有可能获得高临床利用率。本综述使用多非利特、氟康唑和氨氯地平来突出改变化学结构在药物处置方面的多方面影响，并引用文献中的例子来强化这些原则。
