Dear G J, Roberts A D, Beaumont C, North S E
Structural ID Group, Toxicokinetics and Biotransformation, PCD DMPK Department, GlaxoSmithKline, Park Road, Ware, Hertfordshire SG12 0DP, UK.
J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Dec 15;876(2):182-90. doi: 10.1016/j.jchromb.2008.10.040. Epub 2008 Oct 31.
Definitive information on the metabolism of a drug candidate in humans is achieved through dosing radiolabelled drug as part of a clinical study, and is typically conducted post-proof of concept in Phase III of the clinical development plan. Here we describe a novel approach, using preparative high performance liquid chromatography and cryoprobe-nuclear magnetic resonance spectroscopy, to determine the human systemic exposure to a drug and its metabolites using samples derived from Phase I clinical studies. Using the described methodology, novel human plasma metabolites, as low as 10 ng/ml can be detected and quantified. This provides an opportunity, early in the development process to understand the potential role of metabolites in the safety and efficacy of drugs in humans.
通过在临床研究中给予放射性标记药物来获取候选药物在人体新陈代谢的确切信息，这通常在临床开发计划的III期概念验证之后进行。在此，我们描述了一种新颖的方法，即使用制备型高效液相色谱和低温探头核磁共振光谱，通过I期临床研究获得的样本，来测定人体对药物及其代谢物的全身暴露情况。使用所描述的方法，可以检测和定量低至10 ng/ml的新型人体血浆代谢物。这为在开发过程早期了解代谢物在人类药物安全性和有效性中的潜在作用提供了机会。
