Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
J Nucl Med. 2020 Nov;61(11):1650-1657. doi: 10.2967/jnumed.120.244038. Epub 2020 Apr 13.
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-methylpurine (C-BMP), a prodrug radiotracer that is intracellularly conjugated with glutathione to form the ABCC1 substrate -(6-(7-C-methylpurinyl))glutathione (C-MPG). Groups of rats, wild-type rats pretreated with the ABCC1 inhibitor MK571, and wild-type control rats underwent dynamic PET scans after administration of C-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. The pulmonary kinetics of radioactivity significantly differed between wild-type and 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]) was 77% higher and the elimination slope of radioactivity washout from the lungs () was 70% lower in rats, whereas after intratracheal administration, AUC was 352% higher and was 86% lower in rats. Pretreatment with MK571 decreased 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. PET with pulmonary administered C-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.
多药耐药相关蛋白 1（三磷酸腺苷结合盒亚家族 C 成员 1 [ABCC1]）在肺上皮屏障中大量表达，它可能影响吸入药物在肺部的分布，并导致治疗反应的个体差异。本研究旨在评估 ABCC1 对 6-溴-7-C-甲基嘌呤（C-BMP）肺部分布的影响，C-BMP 是一种前药示踪剂，在细胞内与谷胱甘肽缀合形成 ABCC1 底物-（6-（7-C-甲基嘌呤基））谷胱甘肽（C-MPG）。一组大鼠、用 ABCC1 抑制剂 MK571 预处理的野生型大鼠和野生型对照大鼠静脉注射或经气管内雾化给予 C-BMP 后进行动态 PET 扫描。使用未标记的 BMP 在人远端肺上皮细胞系 NCI-H441 上进行体外转运实验。放射性示踪剂给药后 0 至 80 分钟，放射性示踪剂给药后肺时间-活性曲线下面积（AUC）在野生型和 大鼠之间的肺动力学差异显著，但经气管内给药后差异更为明显。静脉注射后， 大鼠的肺暴露（放射性示踪剂给药后 0 至 80 分钟的肺时间-活性曲线下面积 [AUC]）增加了 77%，放射性示踪剂从肺部洗脱的消除斜率（）降低了 70%，而经气管内给药后， 大鼠的 AUC 增加了 352%， 降低了 86%。经气管内给予放射性示踪剂前用 MK571 预处理可使 降低 20%。在存在 MK571 的情况下，NCI-H441 细胞中 MPG 的细胞内积累显著增加，细胞外流出减少。用肺部给予的 C-BMP 进行 PET 可测量肺上皮屏障处的 ABCC1 活性，并且可能适用于人类，以评估疾病、遗传多态性或同时药物摄入对肺 ABCC1 活性的影响。
