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

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 <i>S</i>-(6-(7-¹¹C-methylpurinyl))glutathione (¹¹C-MPG). <b>Methods:</b> Groups of <i>Abcc1</i>^<i>(-/-)</i> 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. <b>Results:</b> The pulmonary kinetics of radioactivity significantly differed between wild-type and <i>Abcc1</i>^<i>(-/-)</i> 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 (<i>k</i>_E,lung) was 70% lower in <i>Abcc1</i>^<i>(-/-)</i> rats, whereas after intratracheal administration, AUC_lung was 352% higher and <i>k</i>_E,lung was 86% lower in <i>Abcc1</i>^<i>(-/-)</i> rats. Pretreatment with MK571 decreased <i>k</i>_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. <b>Conclusion:</b> 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.