Influence of Multidrug Resistance-Associated Proteins on the Excretion of the ABCC1 Imaging Probe 6-Bromo-7-[11C]Methylpurine in Mice

Viktoria Zoufal; Severin Mairinger; Markus Krohn; Thomas Wanek; Thomas Filip; Michael Sauberer; Johann Stanek; Alexander Traxl; John D. Schuetz; Claudia Kuntner; Jens Pahnke; Oliver Langer

doi:10.1007/s11307-018-1230-y

Influence of Multidrug Resistance-Associated Proteins on the Excretion of the ABCC1 Imaging Probe 6-Bromo-7-[¹¹C]Methylpurine in Mice

Viktoria Zoufal, Severin Mairinger, Markus Krohn, Thomas Wanek, Thomas Filip, Michael Sauberer, Johann Stanek, Alexander Traxl, John D. Schuetz, Claudia Kuntner, Jens Pahnke, Oliver Langer^*

^*Corresponding author for this work

Institute of Experimental Dermatology

17 Citations (Scopus)

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-[¹¹C]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-[¹¹C]methylpurine. Procedures: We performed PET scans with 6-bromo-7-[¹¹C]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-[¹¹C]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_{elimination,blood}). In the kidneys, there were significant decreases in the rate constant for radioactivity uptake from the blood (k_{uptake,kidney}), k_{elimination,kidney}, and the rate constant for tubular secretion of radioactivity (k_urine). Experiments in Abcc4^(−/−) mice indicated that Abcc4 contributed to renal excretion of 6-bromo-7-[¹¹C]methylpurine-derived radioactivity. Conclusions: Our data suggest that 6-bromo-7-[¹¹C]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-[¹¹C]methylpurine-derived radioactivity.

Original language	English
Journal	Molecular Imaging and Biology
Volume	21
Issue number	2
Pages (from-to)	306-316
Number of pages	11
ISSN	1536-1632
DOIs	https://doi.org/10.1007/s11307-018-1230-y
Publication status	Published - 15.04.2019

Funding

Acknowledgments. Open access funding provided by Austrian Science Fund (FWF). The authors wish to thank Mathilde Löbsch for help in conducting the PET experiments and Dr. Toshimitsu Okamura (National Institute of Radiological Sciences, Chiba, Japan) for providing reference standards for the radiosynthesis and metabolite analysis of 6-bromo-7-[11C]methylpurine. Funding. This work was supported by the Austrian Science Fund (FWF) [grant number I 1609-B24, to O. Langer], the Deutsche Forschungsgesellschaft (DFG) [grant number DFG PA930/9-1, to J. Pahnke], and the Lower Austria Corporation for Research and Education (NFB) [grant number LS14-008, to T. Wanek].

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

Access to Document

10.1007/s11307-018-1230-y

Cite this

Zoufal, V., Mairinger, S., Krohn, M., Wanek, T., Filip, T., Sauberer, M., Stanek, J., Traxl, A., Schuetz, J. D., Kuntner, C., Pahnke, J., & Langer, O. (2019). Influence of Multidrug Resistance-Associated Proteins on the Excretion of the ABCC1 Imaging Probe 6-Bromo-7-[¹¹C]Methylpurine in Mice. Molecular Imaging and Biology, 21(2), 306-316. https://doi.org/10.1007/s11307-018-1230-y

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title = "Influence of Multidrug Resistance-Associated Proteins on the Excretion of the ABCC1 Imaging Probe 6-Bromo-7-[11C]Methylpurine in Mice",

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-[11C]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-[11C]methylpurine. Procedures: We performed PET scans with 6-bromo-7-[11C]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-[11C]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 (kelimination,blood). In the kidneys, there were significant decreases in the rate constant for radioactivity uptake from the blood (kuptake,kidney), kelimination,kidney, and the rate constant for tubular secretion of radioactivity (kurine). Experiments in Abcc4(−/−) mice indicated that Abcc4 contributed to renal excretion of 6-bromo-7-[11C]methylpurine-derived radioactivity. Conclusions: Our data suggest that 6-bromo-7-[11C]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-[11C]methylpurine-derived radioactivity.",

author = "Viktoria Zoufal and Severin Mairinger and Markus Krohn and Thomas Wanek and Thomas Filip and Michael Sauberer and Johann Stanek and Alexander Traxl and Schuetz, \{John D.\} and Claudia Kuntner and Jens Pahnke and Oliver Langer",

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doi = "10.1007/s11307-018-1230-y",

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Zoufal, V, Mairinger, S, Krohn, M, Wanek, T, Filip, T, Sauberer, M, Stanek, J, Traxl, A, Schuetz, JD, Kuntner, C, Pahnke, J & Langer, O 2019, 'Influence of Multidrug Resistance-Associated Proteins on the Excretion of the ABCC1 Imaging Probe 6-Bromo-7-[¹¹C]Methylpurine in Mice', Molecular Imaging and Biology, vol. 21, no. 2, pp. 306-316. https://doi.org/10.1007/s11307-018-1230-y

TY - JOUR

T1 - Influence of Multidrug Resistance-Associated Proteins on the Excretion of the ABCC1 Imaging Probe 6-Bromo-7-[11C]Methylpurine in Mice

AU - Zoufal, Viktoria

AU - Mairinger, Severin

AU - Krohn, Markus

AU - Wanek, Thomas

AU - Filip, Thomas

AU - Sauberer, Michael

AU - Stanek, Johann

AU - Traxl, Alexander

AU - Schuetz, John D.

AU - Kuntner, Claudia

AU - Pahnke, Jens

AU - Langer, Oliver

PY - 2019/4/15

Y1 - 2019/4/15

N2 - 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-[11C]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-[11C]methylpurine. Procedures: We performed PET scans with 6-bromo-7-[11C]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-[11C]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 (kelimination,blood). In the kidneys, there were significant decreases in the rate constant for radioactivity uptake from the blood (kuptake,kidney), kelimination,kidney, and the rate constant for tubular secretion of radioactivity (kurine). Experiments in Abcc4(−/−) mice indicated that Abcc4 contributed to renal excretion of 6-bromo-7-[11C]methylpurine-derived radioactivity. Conclusions: Our data suggest that 6-bromo-7-[11C]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-[11C]methylpurine-derived radioactivity.

AB - 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-[11C]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-[11C]methylpurine. Procedures: We performed PET scans with 6-bromo-7-[11C]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-[11C]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 (kelimination,blood). In the kidneys, there were significant decreases in the rate constant for radioactivity uptake from the blood (kuptake,kidney), kelimination,kidney, and the rate constant for tubular secretion of radioactivity (kurine). Experiments in Abcc4(−/−) mice indicated that Abcc4 contributed to renal excretion of 6-bromo-7-[11C]methylpurine-derived radioactivity. Conclusions: Our data suggest that 6-bromo-7-[11C]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-[11C]methylpurine-derived radioactivity.

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DO - 10.1007/s11307-018-1230-y

M3 - Journal articles

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