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Chem Res Toxicol. 2012 Mar 19;25(3):543-55. doi: 10.1021/tx200509f. Epub 2012 Feb 9.
Radioactivity has been used in drug discovery and development for several decades because it offers researchers a highly sensitive way to quantitatively assess the absorption, distribution, metabolism, and/or excretion (ADME) of chemical entities by incorporating a radioactive isotope into the structure of the drug molecule. Regulatory agencies around the world require drug makers to characterize the ADME properties of prospective new drugs as one way to help ensure that patients are not exposed to dangerous drug and/or drug metabolite levels before they can be approved for human use. Radiolabeled compounds have consistently proved to be the most efficient tool for determining that information, even though attempts have been made to use nonradioactive techniques. The techniques of quantitative whole-body autoradiography (QWBA) and microautoradiography (MARG), which rely on the use of radiolabeled drugs, are two techniques that are routinely used to examine tissue distribution of drugs in discovery and development. These techniques provide drug researchers with quantitative tissue concentration data and a visual location of those concentrations in intact organs, tissues, and cells of laboratory animals. It is important for readers to realize that these techniques visualize total radioactivity, which can include the parent molecule along with its metabolites, and/or degradation products or impurities. This requires investigators to treat the quantitative data with caution unless the identity of the radioactivity is determined using some type of other bioanalytical techniques, such as mass spectroscopy and/or radio-HPLC, which can be easily performed on the tissue obtained from the animals used for QWBA and/or MARG. Nevertheless, these data are used in drug discovery and development to answer questions related to tissue penetration, fetal/placental transfer, tissue retention, routes of elimination, drug-drug interactions, enzyme induction/inhibition, formulation comparisons, in vivo compound solubility, differential metabolite distribution, interspecies comparisons, and to predict human exposure to parent drugs, metabolites, and radiation during clinical studies. This review will consider the strategic use of WBA, QWBA, and MARG in the pharmaceutical industry. Case studies and anecdotal information will also be presented; however, readers should realize that these are general examples and that some details have been omitted for brevity and/or because the data is proprietary and could not be presented at this time. Nevertheless, the images and discussions are provided to demonstrate how the techniques can and have been used to examine in situ tissue distribution of therapeutic compounds.
放射性核素在药物发现和开发中已经使用了几十年，因为它为研究人员提供了一种高度敏感的方法，可以通过将放射性同位素掺入药物分子的结构中来定量评估化学实体的吸收、分布、代谢和/或排泄（ADME）。世界各国的监管机构都要求制药商对潜在新药的 ADME 特性进行特征描述，这是帮助确保在获得人类使用批准之前，患者不会接触到危险的药物和/或药物代谢物水平的一种方法。放射性标记化合物已被证明是确定这些信息的最有效工具，尽管人们曾尝试使用非放射性技术。定量全身放射自显影术（QWBA）和微量放射自显影术（MARG）这两种技术依赖于放射性标记药物的使用，是在发现和开发中用于检查药物组织分布的两种常规技术。这些技术为药物研究人员提供了定量的组织浓度数据，并提供了药物在实验室动物的完整器官、组织和细胞中的浓度的直观位置。重要的是，读者应该意识到这些技术可以可视化总放射性，其中包括母体分子及其代谢物和/或降解产物或杂质。这要求研究人员谨慎对待定量数据，除非使用某种类型的其他生物分析技术（如质谱和/或放射性高效液相色谱法）确定放射性的身份，这些技术可以很容易地在用于 QWBA 和/或 MARG 的动物组织上进行。尽管如此，这些数据仍用于药物发现和开发中，以回答与组织穿透、胎儿/胎盘转移、组织保留、消除途径、药物相互作用、酶诱导/抑制、配方比较、体内化合物溶解度、代谢物分布差异、种间比较以及预测临床研究中母体药物、代谢物和辐射对人体的暴露有关的问题。本综述将考虑在制药行业中战略性地使用 WBA、QWBA 和 MARG。还将提出案例研究和轶事信息；但是，读者应该意识到，这些只是一般示例，并且为了简洁起见和/或因为数据是专有的，目前无法呈现一些细节。然而，提供这些图像和讨论是为了展示这些技术如何以及已经被用于检查治疗化合物的原位组织分布。
