Dueker Stephen R, Lohstroh Peter N, Giacomo Jason A, Le T Vuong, Keck Bradly D, Vogel John S
Vitalea Science Inc., 2121 Second Street, B101 Davis, CA 95618, USA.
Bioanalysis. 2010 Mar;2(3):441-54. doi: 10.4155/bio.10.8.
Quantitative assessment of metabolites of drug candidates in early-phase clinical development presents an analytical challenge when methods, standards and assays are not yet available. Radioisotopic labeling, principally with radiocarbon ((14)C), is the preferred method for discovering and quantifying the absolute yields of metabolites in the absence of reference material or a priori knowledge of the human metabolism. However, the detection of (14)C is inefficient by decay counting methods and, as a result, high radiological human (14)C-doses had been needed to assure sensitive detection of metabolites over time. High radiological doses and the associated costs have been a major obstacle to the routine (and early) use of (14)C despite the recognized advantages of a (14)C-tracer for quantifying drug metabolism and disposition. Accelerator mass spectrometry eliminates this long-standing problem by reducing radioactivity levels while delivering matrix-independent quantitation to attomole levels of sensitivity in small samples or fractionated isolates. Accelerator mass spectrometry and trace (14)C-labeled drugs are now used to obtain early insights into the human metabolism of a drug candidate in ways that were not previously practical. With this article we describe some of our empirically based approaches for regualted bioanalysis and offer perspectives on current applications and opportunities for the future.
在早期临床开发中，当药物候选物的代谢物定量评估方法、标准品和检测方法尚不可用时，这会带来分析上的挑战。放射性同位素标记，主要是用放射性碳（¹⁴C），是在缺乏参考物质或对人体代谢没有先验知识的情况下发现和定量代谢物绝对产率的首选方法。然而，通过衰变计数法检测¹⁴C效率低下，因此，为了确保随着时间推移能灵敏地检测代谢物，需要高放射性的人体¹⁴C剂量。尽管¹⁴C示踪剂在定量药物代谢和处置方面具有公认的优势，但高放射性剂量及相关成本一直是¹⁴C常规（和早期）应用的主要障碍。加速器质谱通过降低放射性水平，同时在小样本或分级分离物中实现与基质无关的飞摩尔级灵敏度定量，消除了这一长期存在的问题。加速器质谱和微量¹⁴C标记药物现在被用于以以前不实用的方式获得对药物候选物人体代谢的早期见解。在本文中，我们描述了一些基于经验的规范生物分析方法，并对当前应用和未来机会提供了观点。
