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Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule?

Abstract

It is generally thought that many drug molecules are transported across biological membranes via passive diffusion at a rate related to their lipophilicity. However, the types of biophysical forces involved in the interaction of drugs with lipid membranes are no different from those involved in their interaction with proteins, and so arguments based on lipophilicity could also be applied to drug uptake by membrane transporters or carriers. In this article, we discuss the evidence supporting the idea that rather than being an exception, carrier-mediated and active uptake of drugs may be more common than is usually assumed — including a summary of specific cases in which drugs are known to be taken up into cells via defined carriers — and consider the implications for drug discovery and development.

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Figure 1: Transmembrane transport of drugs.
Figure 2: Comparisons between drug permeability in natural membranes and artificial systems, and their comparison with oil–water partition coefficients.
Figure 3: Comparisons between drug permeability in natural membranes and artificial systems, and their comparison with oil–water partition coefficients.
Figure 4: Multiple drug carriers in different tissues, all of which may need to be permeated.
Figure 5: Tissue-selective expression of solute carrier molecules, where brown colouration indicates presence of protein.
Figure 6: The 'bottom-up' systems biology agenda.

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Acknowledgements

Our interest in pursuing these issues has been helped considerably by grant BB/D007,747/1 from the BBSRC, together with attendant funding from GlaxoSmithKline (GSK). We thank S. Summerfield and P. Jeffrey of GSK for their support and interest, and K. Lanthaler and S. Oliver for useful discussions. D.B.K. also thanks the EPSRC and RSC for financial support, and the Royal Society/Wolfson Foundation for a Research Merit Award. We apologise to the many authors whose work was not cited due to limitations on references. This is a contribution from the BBSRC- and EPSRC-funded Manchester Centre for Integrative Systems Biology (www.mcisb.org/).

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Correspondence to Douglas B. Kell.

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Some of the work presented was funded by GlaxoSmithKline and by the Biotechnology and Biological Sciences Research Council.

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Dobson, P., Kell, D. Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule?. Nat Rev Drug Discov 7, 205–220 (2008). https://doi.org/10.1038/nrd2438

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