MSACL 2015 EU Plenary Abstract

The Cellular Uptake of Pharmaceutical Drugs Is Transporter-Mediated and Is Thus a Problem Not of Biophysics But of Systems Biology

Douglas Kell
The University of Manchester

Long Abstract

A fundamental question remains as to whether xenobiotic drugs cross cellular membranes mainly (or exclusively) by transporter-independent diffusion across whatever bilayer lipoidal parts of cellular membranes may be present, or whether they normally (or exclusively) ‘hitchhike’ rides using the carriers normally involved in the metabolism of natural metabolites. The former (for which, astonishingly, there is in fact no actual experimental evidence) would involve a biophysical mechanism, based mainly on lipophilicity, while the latter requires a mechanistic understanding of which carriers are involved, and is thus a problem of network or systems biology. In other words [1], “is carrier-mediated transport of pharmaceutical drugs the exception or the rule?”

A huge amount of literature (e.g. [1-5] and references therein), that I shall summarise, indicates that there is no serious evidence against the view that trans-phosphobilayer-mediated transfer of pharmaceutical drugs across biological membranes is negligible (‘PBIN’), while there is abundant and increasing evidence for the carrier-mediated route. A recent approach in yeast illustrates this experimentally [6], while the digital availability of principled metabolic network models [7-9] allows one to determine [10; 11], consistent with this, that successful pharmaceutical drugs are much more like metabolites than are the ‘Lipinski-compliant’ molecules typically available in drug discovery libraries. This suggests (or is at least consistent with the view) that cellular drug uptake is more or less exclusively transporter-mediated, and that knowledge of both the metabolome and of the concentrations and activities of transporters used by individual xenobiotics will be of much value in designing better drugs [12-14] and bioprocesses [15].

[1] Dobson, P. D. & Kell, D. B. (2008). Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat Rev Drug Disc 7, 205-220.

[2] Dobson, P., Lanthaler, K., Oliver, S. G. & Kell, D. B. (2009). Implications of the dominant role of cellular transporters in drug uptake. Curr Top Med Chem 9, 163-184.

[3] Kell, D. B. & Dobson, P. D. (2009). The cellular uptake of pharmaceutical drugs is mainly carrier-mediated and is thus an issue not so much of biophysics but of systems biology. In Proc Int Beilstein Symposium on Systems Chemistry (ed. M. G. Hicks and C. Kettner), pp. 149-168. Logos Verlag, Berlin.

[4] Kell, D. B., Dobson, P. D. & Oliver, S. G. (2011). Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only. Drug Disc Today 16, 704-714.

[5] Kell, D. B., Dobson, P. D., Bilsland, E. & Oliver, S. G. (2013). The promiscuous binding of pharmaceutical drugs and their transporter-mediated uptake into cells: what we (need to) know and how we can do so. Drug Disc Today 18, 218-239.

[6] Lanthaler, K., Bilsland, E., Dobson, P., Moss, H. J., Pir, P., Kell, D. B. & Oliver, S. G. (2011). Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast. BMC Biol 9, 70.

[7] Herrgård, M. J….& Kell, D. B. (2008). A consensus yeast metabolic network obtained from a community approach to systems biology. Nat Biotechnol. 26, 1155-1160.

[8] Swainston, N., Mendes, P. & Kell, D. B. (2013). An analysis of a ‘community-driven’ reconstruction of the human metabolic network. Metabolomics 9, 757-764.

[9] Thiele, I….Kell, D. B., Mendes, P. & Palsson, B. Ø. (2013). A community-driven global reconstruction of human metabolism. Nat Biotechnol. 31, 419-425.

[10] O'Hagan, S., Swainston, N., Handl, J. & Kell, D. B. (2015). A 'rule of 0.5' for the metabolite-likeness of approved pharmaceutical drugs. Metabolomics 11, 323-339.

[11] O'Hagan S, Kell DB (2015) Understanding the foundations of the structural similarities between marketed drugs and endogenous human metabolites. Front Pharmacol; 6:105.

[12] Kell, D. B. (2013). Finding novel pharmaceuticals in the systems biology era using multiple effective drug targets, phenotypic screening, and knowledge of transporters: where drug discovery went wrong and how to fix it. FEBS J 280, 5957-5980.

[13] Kell, D. B. & Goodacre, R. (2014). Metabolomics and systems pharmacology: why and how to model the human metabolic network for drug discovery. Drug Disc Today 19, 171-182.

[14] Kell, D. B. & Oliver, S. G. (2014). How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion. Front Pharmacol 5, 231.

[15] Kell, D. B., Swainston, N., Pir, P. & Oliver, S. G. (2015) Membrane transporter engineering in industrial biotechnology and whole-cell biocatalysis. Trends Biotechnol 2015; 33:237-246.