Severin Mairinger1, Johannes A Sake2, Irene Hernández Lozano3, Thomas Filip1, Michael Sauberer1, Johann Stanek1, Thomas Wanek1, Carsten Ehrhardt2, Oliver Langer4,3,5. 1. Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria. 2. School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. 3. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; and. 4. Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria oliver.langer@ait.ac.at. 5. Division of Nuclear Medicine, Department of Biomedical Imaging und Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
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 (k E,lung) was 70% lower in Abcc1 (-/-) rats, whereas after intratracheal administration, AUClung was 352% higher and k E,lung was 86% lower in Abcc1 (-/-) rats. Pretreatment with MK571 decreased k E,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.
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 (k E,lung) was 70% lower in Abcc1 (-/-) rats, whereas after intratracheal administration, AUClung was 352% higher and k E,lung was 86% lower in Abcc1 (-/-) rats. Pretreatment with MK571 decreased k E,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.
Authors: Michael Wölfl-Duchek; Severin Mairinger; Irene Hernández-Lozano; Thomas Filip; Viktoria Zoufal; Mathilde Löbsch; Johann Stanek; Claudia Kuntner; Thomas Wanek; Martin Bauer; Jens Pahnke; Oliver Langer Journal: Int J Mol Sci Date: 2022-06-10 Impact factor: 6.208
Authors: Przemysław Koźmiński; Dorota Niedziałek; Grzegorz Wieczorek; Paweł K Halik; Kamila Czarnecka; Aleksandra Rogut; Łukasz Cheda; Zbigniew Rogulski; Paweł Szymański; Ewa Gniazdowska Journal: Int J Mol Sci Date: 2022-07-29 Impact factor: 6.208