Journal
JOURNAL OF NUCLEAR MEDICINE
Volume 61, Issue 11, Pages 1650-1657Publisher
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.120.244038
Keywords
6-bromo-7-C-11-methylpurine; lung epithelial barrier; multidrug resistance-associated protein 1; PET; pulmonary drug disposition
Funding
- Lower Austria Corporation for Research and Education (NO Forschungs-und Bildungsges.mbH [NFB]) [LS17-009]
Ask authors/readers for more resources
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-C-11-methylpurine (C-11-BMP), a prodrug radiotracer that is intracellularly conjugated with glutathione to form the ABCC1 substrate S-(6-(7-C-11-methylpurinyl))glutathione (C-11-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 C-11-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 [AUC(lung)]) 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 kE, 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 C-11-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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available