Use of Radiolabeled Compounds in Drug Metabolism and Pharmacokinetic Studies
Use of Radiolabeled Compounds in Drug Metabolism and Pharmacokinetic Studies
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DOI：
10.1021/tx2005212
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发表时间：
2012-03-01
影响因子：
4.1
通讯作者：
Weidolf, Lars
中科院分区：
文献类型：
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作者：
Isin, Emre M.;Elmore, Charles S.;Weidolf, Lars
作为药物发现和开发过程的一部分，重要的是要了解候选药物在人体中的命运以及用于临床前毒性和药效学研究的动物种属的相关性。因此，在药物开发过程的不同阶段进行了各种体外和体内研究，以阐明候选药物的吸收、分布、代谢和排泄特性。尽管这些研究通常采用最先进的LC/MS技术，但在不依赖结构信息和MS电离特性的情况下，仍然经常需要放射性标记分子来定量代谢物并评估所有药物相关物质的保留和排泄。从这个角度来看，我们描述了阿斯利康同位素化学的活动，并简要概述了不同的常用方法制备C-14和H-3标记的候选药物。此外，还提供了使用放射性标记候选药物的各种药物代谢和药代动力学研究以及相关的内部示例。最后，我们概述了我们在药物代谢和药代动力学研究中使用放射性标记化合物的战略变化，重点是延迟使用放射性标记药物分子的体内研究。
As part of the drug discovery and development process, it is important to understand the fate of the drug candidate in humans and the relevance of the animal species used for preclinical toxicity and pharmacodynamic studies. Therefore, various in vitro and in vivo studies are conducted during the different stages of the drug development process to elucidate the absorption, distribution, metabolism, and excretion properties of the drug candidate. Although state-of-the-art LC/MS techniques are commonly employed for these studies, radiolabeled molecules are still frequently required for the quantification of metabolites and to assess the retention and excretion of all drug related material without relying on structural information and MS ionization properties. In this perspective, we describe the activities of Isotope Chemistry at AstraZeneca and give a brief overview of different commonly used approaches for the preparation of C-14- and H-3-labeled drug candidates. Also various drug metabolism and pharmacokinetic studies utilizing radiolabeled drug candidates are presented with in-house examples where relevant. Finally, we outline strategic changes to our use of radiolabeled compounds in drug metabolism and pharmacokinetic studies, with an emphasis on delaying of in vivo studies employing radiolabeled drug molecules.