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Research ArticlePulmonary

Assessing the Activity of Multidrug Resistance–Associated Protein 1 at the Lung Epithelial Barrier

Severin Mairinger, Johannes A. Sake, Irene Hernández Lozano, Thomas Filip, Michael Sauberer, Johann Stanek, Thomas Wanek, Carsten Ehrhardt and Oliver Langer
Journal of Nuclear Medicine November 2020, 61 (11) 1650-1657; DOI: https://doi.org/10.2967/jnumed.120.244038
Severin Mairinger
1Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
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Johannes A. Sake
2School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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Irene Hernández Lozano
3Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; and
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Thomas Filip
1Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
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Michael Sauberer
1Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
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Johann Stanek
1Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
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Thomas Wanek
1Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
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Carsten Ehrhardt
2School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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Oliver Langer
1Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
3Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; and
4Division of Nuclear Medicine, Department of Biomedical Imaging und Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
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Abstract

Multidrug resistance–associated protein 1 (adenosine triphosphate–binding cassette subfamily C member 1 [ABCC1]) is abundantly expressed at the lung epithelial barrier, where it may influence the pulmonary disposition of inhaled drugs and contribute to variability in therapeutic response. The aim of this study was to assess the impact of ABCC1 on the pulmonary disposition of 6-bromo-7-11C-methylpurine (11C-BMP), a prodrug radiotracer that is intracellularly conjugated with glutathione to form the ABCC1 substrate S-(6-(7-11C-methylpurinyl))glutathione (11C-MPG). Methods: Groups of Abcc1(−/−) rats, wild-type rats pretreated with the ABCC1 inhibitor MK571, and wild-type control rats underwent dynamic PET scans after administration of 11C-BMP intravenously or by intratracheal aerosolization. In vitro transport experiments were performed with unlabeled BMP on the human distal lung epithelial cell line NCI-H441. Results: The pulmonary kinetics of radioactivity significantly differed between wild-type and Abcc1(−/−) rats, but differences were more pronounced after intratracheal than after intravenous administration. After intravenous administration, lung exposure (area under the lung time–activity curve from 0 to 80 min after radiotracer administration [AUClung]) was 77% higher and the elimination slope of radioactivity washout from the lungs (kE,lung) was 70% lower in Abcc1(−/−) rats, whereas after intratracheal administration, AUClung was 352% higher and kE,lung was 86% lower in Abcc1(−/−) rats. Pretreatment with MK571 decreased kE,lung by 20% after intratracheal radiotracer administration. Intracellular accumulation of MPG in NCI-H441 cells was significantly higher and extracellular efflux was lower in the presence than in the absence of MK571. Conclusion: PET with pulmonary administered 11C-BMP can measure ABCC1 activity at the lung epithelial barrier and may be applicable in humans to assess the effects of disease, genetic polymorphisms, or concomitant drug intake on pulmonary ABCC1 activity.

  • 6-bromo-7-11C-methylpurine
  • lung epithelial barrier
  • multidrug resistance–associated protein 1
  • PET
  • pulmonary drug disposition

Footnotes

  • Published online Apr. 13, 2020.

  • © 2020 by the Society of Nuclear Medicine and Molecular Imaging.
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Journal of Nuclear Medicine: 61 (11)
Journal of Nuclear Medicine
Vol. 61, Issue 11
November 1, 2020
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Assessing the Activity of Multidrug Resistance–Associated Protein 1 at the Lung Epithelial Barrier
Severin Mairinger, Johannes A. Sake, Irene Hernández Lozano, Thomas Filip, Michael Sauberer, Johann Stanek, Thomas Wanek, Carsten Ehrhardt, Oliver Langer
Journal of Nuclear Medicine Nov 2020, 61 (11) 1650-1657; DOI: 10.2967/jnumed.120.244038

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Assessing the Activity of Multidrug Resistance–Associated Protein 1 at the Lung Epithelial Barrier
Severin Mairinger, Johannes A. Sake, Irene Hernández Lozano, Thomas Filip, Michael Sauberer, Johann Stanek, Thomas Wanek, Carsten Ehrhardt, Oliver Langer
Journal of Nuclear Medicine Nov 2020, 61 (11) 1650-1657; DOI: 10.2967/jnumed.120.244038
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Keywords

  • 6-Bromo-7-11C-methylpurine
  • Lung epithelial barrier
  • multidrug resistance–associated protein 1
  • PET
  • Pulmonary drug disposition
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