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多药耐药相关蛋白对 ABCC1 成像探针 6-溴-7-[C]甲基嘌呤在小鼠体内排泄的影响。

Influence of Multidrug Resistance-Associated Proteins on the Excretion of the ABCC1 Imaging Probe 6-Bromo-7-[C]Methylpurine in Mice.

机构信息

Biomedical Systems, Center for Health & Bioresources, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.

Department of Neuro-/Pathology, University of Oslo (UiO) and Oslo University Hospital (OUS), Oslo, Norway.

出版信息

Mol Imaging Biol. 2019 Apr;21(2):306-316. doi: 10.1007/s11307-018-1230-y.

DOI:10.1007/s11307-018-1230-y
PMID:29942989
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6449286/
Abstract

PURPOSE

Multidrug resistance-associated proteins (MRPs) mediate the hepatobiliary and renal excretion of many drugs and drug conjugates. The positron emission tomography (PET) tracer 6-bromo-7-[C]methylpurine is rapidly converted in tissues by glutathione-S-transferases into its glutathione conjugate, and has been used to measure the activity of Abcc1 in the brain and the lungs of mice. Aim of this work was to investigate if the activity of MRPs in excretory organs can be measured with 6-bromo-7-[C]methylpurine.

PROCEDURES

We performed PET scans with 6-bromo-7-[C]methylpurine in groups of wild-type, Abcc4 and Abcc1 mice, with and without pre-treatment with the prototypical MRP inhibitor MK571.

RESULTS

6-Bromo-7-[C]methylpurine-derived radioactivity predominantly underwent renal excretion. In blood, MK571 treatment led to a significant increase in the AUC and a decrease in the elimination rate constant of radioactivity (k). In the kidneys, there were significant decreases in the rate constant for radioactivity uptake from the blood (k), k, and the rate constant for tubular secretion of radioactivity (k). Experiments in Abcc4 mice indicated that Abcc4 contributed to renal excretion of 6-bromo-7-[C]methylpurine-derived radioactivity.

CONCLUSIONS

Our data suggest that 6-bromo-7-[C]methylpurine may be useful to assess the activity of MRPs in the kidneys as well as in other organs (brain, lungs), although further work is needed to identify the MRP subtypes involved in the disposition of 6-bromo-7-[C]methylpurine-derived radioactivity.

摘要

目的

多药耐药相关蛋白（MRPs）介导许多药物和药物缀合物的肝胆和肾脏排泄。正电子发射断层扫描（PET）示踪剂 6-溴-7-[C]甲基嘌呤在组织中被谷胱甘肽-S-转移酶迅速转化为其谷胱甘肽缀合物，并已用于测量小鼠大脑和肺部的 Abcc1 活性。本工作的目的是研究 MRPs 在排泄器官中的活性是否可以用 6-溴-7-[C]甲基嘌呤来测量。

过程

我们在野生型、Abcc4 和 Abcc1 小鼠组中进行了 6-溴-7-[C]甲基嘌呤的 PET 扫描，并用和不用典型的 MRP 抑制剂 MK571 进行预处理。

结果

6-溴-7-[C]甲基嘌呤衍生的放射性主要经肾脏排泄。在血液中，MK571 处理导致放射性的 AUC 显著增加，消除率常数（k）降低。在肾脏中，放射性从血液中摄取的速率常数（k）、k 和放射性的管状分泌速率常数（k）均显著降低。Abcc4 小鼠的实验表明 Abcc4 有助于 6-溴-7-[C]甲基嘌呤衍生放射性的肾脏排泄。

结论

我们的数据表明，6-溴-7-[C]甲基嘌呤可能有助于评估肾脏以及其他器官（脑、肺）中 MRPs 的活性，尽管需要进一步的工作来确定参与 6-溴-7-[C]甲基嘌呤衍生放射性处置的 MRP 亚型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/fcdad528c968/11307_2018_1230_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/053753dbc3eb/11307_2018_1230_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/e0519eb0c3fb/11307_2018_1230_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/22806a993df0/11307_2018_1230_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/4acafe0672c5/11307_2018_1230_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/c90f6a2d5bfe/11307_2018_1230_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/fcdad528c968/11307_2018_1230_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/053753dbc3eb/11307_2018_1230_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/e0519eb0c3fb/11307_2018_1230_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/22806a993df0/11307_2018_1230_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/4acafe0672c5/11307_2018_1230_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/c90f6a2d5bfe/11307_2018_1230_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2559/6449286/fcdad528c968/11307_2018_1230_Fig6_HTML.jpg

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