Abstract
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”.
Highlights
Over the years, two main ideas have been used to explain the mechanisms by which pharmaceutical drugs and/or substrates and products of biotechnological interest pass through the plasma membranes of the relevant organism: in a more classical analysis, it is assumed that molecules can diffuse through the core of the lipid bilayer by some means
The only reasonable explanation is that the SLC35F2 transporter normally carried some 99.5% of the flux of YM155 into the cell, and that the transmembrane flux occurring by any other means, including via bilayer transport, is negligible
The transport of small organic molecules across them commonly requires the intercession of proteinaceous transporters (e.g., [2,3,6,8,101,287,370,592–620]), and there is no actual evidence whatsoever for any significant flux across native, undamaged biomembranes through whatever phospholipid bilayer may be present
Summary
Two main ideas have been used to explain the mechanisms by which pharmaceutical drugs and/or substrates and products of biotechnological interest pass through the plasma (or other) membranes of the relevant organism: in a more classical analysis, it is assumed (and it really is purely an assumption [1]) that molecules can diffuse through the core of the lipid bilayer by some means. In an alternative and really entirely opposite view, which we refer to as PBIN for “phospholipid bilayer diffusion is negligible” [2], we have argued [1–12] (and these constitute background that we mainly do not rehearse again here) that this does not occur in real biomembranes to any significant extent at all. Some of this background material is available in a webinar (https://bit.ly/3yQJ1FG, accessed on 15 September 2021). We shall start by looking at why this is the case, initially by focusing on some of the major differences between real biomembranes and those artificial ones made from phospholipid bilayers
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