Institute of Pharmaceutical Science , King's College London , Franklin-Wilkins Building, 150 Stamford Street , London SE1 9NH , United Kingdom.
Sackler Institute of Pulmonary Pharmacology , King's College London , Franklin-Wilkins Building, 150 Stamford Street , London SE1 9NH , United Kingdom.
Mol Pharm. 2018 Mar 5;15(3):861-870. doi: 10.1021/acs.molpharmaceut.7b00715. Epub 2018 Feb 9.
Certain xenobiotics, such as paraquat, are sequestered into the lungs from the systemic circulation by the polyamine transporter system (PTS). The aim of this study was to investigate whether ion-pairing a drug (theophylline) with a PTS substrate (spermine) provides a means of using this active transport mechanism to target drug delivery to the lungs. Fourier transform infrared spectroscopy showed that two of the amine groups of spermine interact with C-N and C═O of theophylline, leaving two free amines to interact with the PTS. In A549 cells, which possess a functional PTS (spermidine K and V, 0.6 ± 0.3 μM and 1.8 ± 0.3 pmol·min per 10 cells, respectively), uptake of the theophylline-spermine ion-pair was increased 1.8-fold compared to free theophylline at 37 °C, but not at 4 °C. In an isolated perfused rat lung model (IPL) a 3.6-fold increase in lung theophylline concentration was observed after vascular administration of the ion-pair compared to free theophylline. Theophylline was cleared from the IPL with similar kinetics irrespective of whether it was delivered as the free drug or an ion-pair, although lung levels remained elevated after washout following delivery as an ion-pair. In vitro simulation of the theophylline-spermine break down demonstrated that a drop in pH from 9.6 to 7.4, such as that undergone by the ion-pair in biological matrices, induces rapid and almost complete dissociation of the ion-paired species. However, infusion of the ion-pair formulations via the vasculature provides almost immediate delivery to the pulmonary capillary bed permitting PTS-mediated active sequestering of ion-paired theophylline into the lungs.
某些外源性化学物质，如百草枯，通过多胺转运系统（PTS）从全身循环中蓄积到肺部。本研究旨在探讨将药物（茶碱）与 PTS 底物（精胺）离子配对是否提供了一种利用这种主动转运机制将药物靶向递送到肺部的方法。傅里叶变换红外光谱表明，精胺的两个胺基与茶碱的 C-N 和 C=O 相互作用，留下两个游离胺基与 PTS 相互作用。在 A549 细胞中，存在功能齐全的 PTS（亚精胺 K 和亚精胺 V，分别为 0.6±0.3 μM 和 1.8±0.3 pmol·min per 10 cells），与游离茶碱相比，37°C 时茶碱-精胺离子对的摄取增加了 1.8 倍，但在 4°C 时没有增加。在离体灌注大鼠肺模型（IPL）中，血管内给予离子对后，肺中茶碱的浓度比给予游离茶碱时增加了 3.6 倍。无论以游离药物还是离子对的形式给药，茶碱从 IPL 中的清除都具有相似的动力学，但在以离子对的形式给药后冲洗时，肺内水平仍保持升高。茶碱-精胺分解的体外模拟表明，pH 值从 9.6 下降到 7.4，如离子对在生物基质中所经历的那样，会导致离子对物种迅速且几乎完全解离。然而，通过血管内输注离子对制剂几乎可以立即将其递送到肺毛细血管床，从而允许 PTS 介导的将离子对结合的茶碱主动蓄积到肺部。
