The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes.
The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes.
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DOI：
10.3390/molecules26185629
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发表时间：
2021-09-16
期刊：
影响因子：
--
通讯作者：
Kell DB
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文献类型：
--
作者：
Kell DB
多年来，我和我的同事们逐渐意识到，药物能够通过体内完整生物膜中存在的任何不受阻碍的磷脂双层扩散的可能性非常低。这是因为（i）大多数真实的生物膜主要是蛋白质，而不是脂质，（ii）与可以形成瞬时水通道的纯脂质双层不同，高浓度的蛋白质用于阻止这种活性，（iii）很久以前选择的自然进化反对仅仅让任何不需要的产物进入细胞的运输方法，（iv）现在已经确定了各种分子的转运蛋白（v）许多实验表明，不同细胞、组织和生物体之间对药物的摄取存在巨大差异，如果脂质双层转运是显著的，或者如果外排是唯一的区分因素，则不能解释这一点，以及（vi）许多将单个转运蛋白的表达水平作为自变量进行操作的实验证明了它们在药物和营养摄取（包括细胞毒性或药物不良反应）中的作用。这使得这样的转运蛋白作为将药物（不仅仅是抗感染药）靶向选定的细胞或组织的手段以及作为药物靶标都是有价值的。同样的考虑也适用于生物技术中底物摄取和产物外排转运蛋白的开发。我们也开始认识到，转运蛋白更混杂，反向转运蛋白的活性比人们认识到的要广泛得多，而且这些过程是适应性的（即，是自然进化的结果）。本评论的目的是总结上述内容，并向读者介绍最近的发展情况。这些发展使我们保留，并确实加强我们的论点，跨膜药物转运“磷脂双层运输是微不足道的”。
Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real biomembranes are mostly protein, not lipid, (ii) unlike purely lipid bilayers that can form transient aqueous channels, the high concentrations of proteins serve to stop such activity, (iii) natural evolution long ago selected against transport methods that just let any undesirable products enter a cell, (iv) transporters have now been identified for all kinds of molecules (even water) that were once thought not to require them, (v) many experiments show a massive variation in the uptake of drugs between different cells, tissues, and organisms, that cannot be explained if lipid bilayer transport is significant or if efflux were the only differentiator, and (vi) many experiments that manipulate the expression level of individual transporters as an independent variable demonstrate their role in drug and nutrient uptake (including in cytotoxicity or adverse drug reactions). This makes such transporters valuable both as a means of targeting drugs (not least anti-infectives) to selected cells or tissues and also as drug targets. The same considerations apply to the exploitation of substrate uptake and product efflux transporters in biotechnology. We are also beginning to recognise that transporters are more promiscuous, and antiporter activity is much more widespread, than had been realised, and that such processes are adaptive (i.e., were selected by natural evolution). The purpose of the present review is to summarise the above, and to rehearse and update readers on recent developments. These developments lead us to retain and indeed to strengthen our contention that for transmembrane pharmaceutical drug transport “phospholipid bilayer transport is negligible”.
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