Nedderman Angus N R
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Ramsgate Road, Sandwich, UK.
Biopharm Drug Dispos. 2009 May;30(4):153-62. doi: 10.1002/bdd.660.
The publication of the FDA MIST guidelines in 2008, together with the acknowledged importance of metabolism data for the progression of novel compounds through drug discovery and drug development, has resulted in a renewed focus on the metabolite identification strategies utilised throughout the pharmaceutical industry. With the plethora of existing and emerging technologies available to the metabolite identification scientist, it is argued that increased diligence should be applied to metabolism studies in the early stages of both drug discovery and drug development, in order to more routinely impact chemical design and to comply with the concepts of the MIST guidance without re-positioning the definitive radiolabelled studies from there typical place in late development.Furthermore, these strategic elements should be augmented by a broad and thorough understanding of the impact of the derived metabolism data, most notably considerations of absolute abundance, structure and pharmacological activity, such that they can be put into proper context as part of a holistic safety strategy.The combination of these approaches should ensure a metabolite identification strategy that successfully applies the principles of the MIST guidance throughout the discovery/development continuum and thereby provides appropriate confidence in support of human safety.
2008年美国食品药品监督管理局（FDA）的《药物代谢物安全性试验（MIST）指南》发布，加之代谢数据对于新型化合物在药物发现和药物开发进程中的重要性已得到公认，这使得整个制药行业重新聚焦于所采用的代谢物鉴定策略。鉴于代谢物鉴定科学家可利用大量现有及新兴技术，有人认为，在药物发现和药物开发的早期阶段，应更加勤勉地开展代谢研究，以便更常规地影响化学设计，并在不改变后期开发中典型的放射性标记研究定位的情况下，符合MIST指南的理念。此外，这些战略要素应通过对衍生代谢数据影响的广泛而深入的理解加以强化，最显著的是对绝对丰度、结构和药理活性的考量，以便能够将它们作为整体安全策略的一部分置于适当的背景中。这些方法的结合应确保代谢物鉴定策略能够在整个发现/开发连续过程中成功应用MIST指南的原则，从而为支持人体安全性提供适当的信心。
