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Article

The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

by 1,2,3
1
Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St, Liverpool L69 7ZB, UK
2
Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet, 2800 Kgs Lyngby, Denmark
3
Mellizyme Biotechnology Ltd., IC1, Liverpool Science Park, Mount Pleasant, Liverpool L3 5TF, UK
Academic Editors: Kristiina Huttunen and Santosh Kumar Adla
Molecules 2021, 26(18), 5629; https://doi.org/10.3390/molecules26185629
Received: 17 August 2021 / Revised: 3 September 2021 / Accepted: 14 September 2021 / Published: 16 September 2021
(This article belongs to the Special Issue Transporter-Mediated Drug Delivery)
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”. View Full-Text
Keywords: membrane transport; pharmaceuticals; drugs; energy coupling; biotechnology; ADME; DMPK; transporter engineering membrane transport; pharmaceuticals; drugs; energy coupling; biotechnology; ADME; DMPK; transporter engineering
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MDPI and ACS Style

Kell, D.B. The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes. Molecules 2021, 26, 5629. https://doi.org/10.3390/molecules26185629

AMA Style

Kell DB. The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes. Molecules. 2021; 26(18):5629. https://doi.org/10.3390/molecules26185629

Chicago/Turabian Style

Kell, Douglas B. 2021. "The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes" Molecules 26, no. 18: 5629. https://doi.org/10.3390/molecules26185629

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