Smith Dennis A, Obach R Scott
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Sandwich, Kent, UK.
Chem Res Toxicol. 2009 Feb;22(2):267-79. doi: 10.1021/tx800415j.
In previous papers, we have offered a strategic framework regarding metabolites of drugs in humans and the need to assess these in laboratory animal species (also termed Metabolites in Safety Testing or MIST; Smith and Obach, Chem. Res. Toxicol. (2006) 19, 1570-1579). Three main tenets of this framework were founded in (i) comparisons of absolute exposures (as circulating concentrations or total body burden), (ii) the nature of the toxicity mechanism (i.e., reversible interaction at specific targets versus covalent binding to multiple macromolecules), and (iii) the biological matrix in which the metabolite was observed (circulatory vs excretory). In the present review, this framework is expanded to include a fourth tenet: considerations for the duration of exposure. Basic concepts of pharmacology are utilized to rationalize the relationship between exposure (to parent drug or metabolite) and various effects ranging from desired therapeutic effects through to severe toxicities. Practical considerations of human ADME (absorption-distribution-metabolism-excretion) data, to determine which metabolites should be further evaluated for safety, are discussed. An analysis of recently published human ADME studies shows that the number of drug metabolites considered to be important for MIST can be excessively high if a simple percentage-of-parent-drug criterion is used without consideration of the aforementioned four tenets. Concern over unique human metabolites has diminished over the years as experience has shown that metabolites of drugs in humans will almost always be observed in laboratory animals, although the proportions may vary. Even if a metabolite represents a high proportion of the dose in humans and a low proportion in animals, absolute abundances in animals frequently exceed that in humans because the doses used in animal toxicology studies are much greater than therapeutic doses in humans. The review also updates the enzymatic basis for the differences between species and how these relate to MIST considerations.
在之前的论文中，我们提出了一个关于人类药物代谢物以及在实验动物物种中评估这些代谢物的必要性的战略框架（也称为安全性测试中的代谢物或MIST；Smith和Obach，《化学研究毒理学》（2006年）19卷，1570 - 1579页）。该框架的三个主要原则基于：（i）绝对暴露量的比较（以循环浓度或全身负荷表示），（ii）毒性机制的性质（即特定靶点处的可逆相互作用与与多种大分子的共价结合），以及（iii）观察到代谢物的生物基质（循环与排泄）。在本综述中，该框架扩展到包括第四个原则：暴露持续时间的考量。利用药理学的基本概念来阐明暴露（于母体药物或代谢物）与从期望的治疗效果到严重毒性等各种效应之间的关系。讨论了人类ADME（吸收 - 分布 - 代谢 - 排泄）数据的实际考量，以确定哪些代谢物应进一步进行安全性评估。对最近发表的人类ADME研究的分析表明，如果不考虑上述四个原则而仅使用母体药物百分比这一简单标准，那么被认为对MIST重要的药物代谢物数量可能会过高。多年来，对独特人类代谢物的担忧有所减少，因为经验表明，尽管比例可能不同，但人类药物的代谢物几乎总是会在实验动物中被观察到。即使一种代谢物在人类中占剂量的比例很高而在动物中占比很低，但由于动物毒理学研究中使用的剂量远高于人类治疗剂量，动物体内的绝对丰度通常会超过人类。本综述还更新了物种间差异的酶学基础以及这些差异与MIST考量的关系。
