Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Implications of endogenous roles of transporters for drug discovery: hitchhiking and metabolite-likeness

Nature Reviews Drug Discovery volume 15, page 143 (2016)Cite this article

Subjects

Access through your institution
Buy or subscribe

In a recent article (Nat. Rev. Drug Discov. 14, 29–44; 2015)1, Nigam asks the question “what do drug transporters really do?”, and discusses the evidence for endogenous roles of transporters in the ATP-binding cassette (ABC) and solute carrier (SLC) transporter families, which have endogenous substrates that include metabolites, antioxidants, signalling molecules, hormones, nutrients and neurotransmitters. Although the article did not focus on the role of transporters in drug uptake, I thought that it could be valuable to highlight some implications for drug discovery of the increasing knowledge on the endogenous substrates and functions of the >500 SLCs2 and ~1,000 transporters encoded overall in the human genome.

In particular, as we have noted in multiple articles — beginning with our article in this journal in 2008 (Ref. 3) — “drugs may 'hitchhike' on carriers or transporters that act on natural endogenous substrates (albeit that these substrates or carriers are often unknown)”. Since then3, the available evidence for the roles of endogenous transporters in transporting drugs has strengthened considerably2, adding substantial support for the hypothesis that not only do drugs use endogenous transporters widely, but also that any diffusion through the phospholipid bilayer of cell membranes is normally negligible (see Ref. 4 for an updated review). Winter et al.5 provide an excellent example of this: genetic removal of just a single transporter decreases by several-100-fold the uptake and toxicity of the candidate anticancer drug YM155 — that is, to less than 1% of their original values.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Nigam, S. K. What do drug transporters really do? Nat. Rev. Drug Discov. 14, 29–44 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. César-Razquin, A. et al. A call for systematic research on solute carriers. Cell 162, 478–487 (2015).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  5. Winter, G. E. et al. The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity. Nat. Chem. Biol. 10, 768–773 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kell, D. B. 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 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Jayaseelan, K. V., Moreno, P., Truszkowski, A., Ertl, P. & Steinbeck, C. Natural product-likeness score revisited: an open-source, open-data implementation. BMC Bioinformatics 13, 106 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  9. O'Hagan, S. & Kell, D. B. The apparent permeabilities of Caco-2 cells to marketed drugs: magnitude, and independence from both biophysical properties and endogenite similarities. PeerJ. 3, e1405 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mendes, P., Oliver, S. G. & Kell, D. B. Fitting transporter activities to cellular drug concentrations and fluxes: why the bumblebee can fly. Trends Pharmacol. Sci. 36, 710–723 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Chemistry, The Manchester Institute of Biotechnology, and the Centre for Synthetic Biology of Fine and Speciality Chemicals (SYNBIOCHEM), The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK

    Douglas B. Kell

Authors
  1. Douglas B. Kell
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Douglas B. Kell.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kell, D. Implications of endogenous roles of transporters for drug discovery: hitchhiking and metabolite-likeness. Nat Rev Drug Discov 15, 143 (2016). https://doi.org/10.1038/nrd.2015.44

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nrd.2015.44

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research