Response to ‘The Need for Speed’, by Matsson et al .
Authors: Pedro Mendes, Stephen G. Oliver, Douglas B. Kell
Journal: Trends in Pharmacological Sciences (2016)

We do not really understand the continuing failure of Matsson and colleagues to recognise where the crucial arguments lie. The chief experimental technique of interest varies transporter expression as an independent variable, and measures the consequent effects on fluxes [1Lanthaler K. et al.Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast.BMC Biol. 2011; 9: 70Crossref PubMed Scopus (51) Google Scholar]. In a recent example of this, Superti-Furga and colleagues knocked out the gene encoding the SLC35F2 transporter, thereby abolishing ∼99.5% of the uptake of an anticancer drug called sepantronium bromide [2Winter G.E. et al.The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity.Nat. Chem. Biol. 2014; 10: 768-773Crossref PubMed Scopus (122) Google Scholar]. Thus any remaining transbilayer flux would be 0.5% at most, which we consider really is negligible, and even that 0.5% is almost certainly carried by other transporters (OCTs) previously considered to be the main transporters [2Winter G.E. et al.The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity.Nat. Chem. Biol. 2014; 10: 768-773Crossref PubMed Scopus (122) Google Scholar]. There is no dodging these kinds of data, nor any of many other self-consistent examples that we have reviewed in our TiPS paper [3Mendes P. et al.Fitting transporter activities to cellular drug concentrations and fluxes: why the bumblebee can fly.Trends Pharmacol. Sci. 2015; 36: 710-723Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar] and elsewwhere [4Dobson P.D. Kell D.B. Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule?.Nat. Rev. Drug Disc. 2008; 7: 205-220Crossref PubMed Scopus (365) Google Scholar, 5Kell D.B. et al.Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only.Drug Disc. Today. 2011; 16: 704-714Crossref PubMed Scopus (142) Google Scholar, 6Kell D.B. et al.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. 2013; 18: 218-239Crossref PubMed Scopus (106) Google Scholar, 7Kell 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. 2013; 280: 5957-5980Crossref PubMed Scopus (82) Google Scholar, 8Kell 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. 2014; 5: 231Crossref PubMed Google Scholar, 9Kell D.B. What would be the observable consequences if phospholipid bilayer diffusion of drugs into cells is negligible?.Trends Pharmacol. Sci. 2015; 36: 15-21Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 10Kell D.B. et al.Membrane transporter engineering in industrial biotechnology and whole-cell biocatalysis.Trends Biotechnol. 2015; 33: 237-246Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 11Kell D.B. The transporter-mediated cellular uptake of pharmaceutical drugs is based on their metabolite-likeness and not on their bulk biophysical properties: towards a systems pharmacology.Perspect. Sci. 2015; 6: 66-83Crossref Google Scholar, 12O’Hagan S. et al.A ‘rule of 0.5′ for the metabolite-likeness of approved pharmaceutical drugs.Metabolomics. 2015; 11: 323-339Crossref PubMed Google Scholar, 13O’Hagan S. Kell D.B. Understanding the foundations of the structural similarities between marketed drugs and endogenous human metabolites.Front. Pharmacol. 2015; 6: 105Crossref PubMed Scopus (22) Google Scholar]. We urge readers to consider these arguments in the round. They also provide very simple explanations for why there is a blood–brain barrier, for instance, on the basis that it simply lacks the relevant transporters, with any background phospholipid bilayer diffusion clearly being negligible. This is why it is seen as a ‘barrier’. Some very brief comments of the letter of Matsson and colleagues: (i) the ludicrously high stirring rates for the propranolol and verapamil values chosen (not of course mimicked in the gut) mean that these values are complete outliers [3Mendes P. et al.Fitting transporter activities to cellular drug concentrations and fluxes: why the bumblebee can fly.Trends Pharmacol. Sci. 2015; 36: 710-723Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]; when the fuller literature for multiple drugs is considered the median rate of drug uptake into Caco-2 cells is almost two orders of magnitude lower [14O’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. 2015; 3: e1405Crossref PubMed Scopus (30) Google Scholar], and thus easily accounted for solely by transporters; (ii) the 42% is for five transporters, mimicking the case used by Matsson et al., who recognised that multiple transporters were likely involved. There is no ‘mistake’. (iii) The Haldane relation is a thermodynamic relation and thus deals with state variables; the numbers of membranes that may be involved (and any mechanistic considerations at all) are thus completely irrelevant. Thermodynamics is like that. The ‘transporters-only’ view has many testable (and tested) predictions, all of which have withstood scrutiny. It also admits the possibility of selective drug targeting. With attrition rates running at 92%, the pharmaceutical industry needs to ensure that it is armed with the best possible intellectual understanding of how drugs enter cells. Hence the recent ‘call to arms’ for research on drug transporters [15César-Razquin A. et al.A call for systematic research on solute carriers.Cell. 2015; 162: 478-487Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar]. Although they choose not to cite any of our prior literature, it seems that the first author does in fact believe that ‘Transport proteins are important mediators of cellular drug influx and efflux and play crucial roles in drug distribution, disposition and clearance’ [16Matsson P. Bergström C.A.S. Computational modeling to predict the functions and impact of drug transporters.Silico Pharmacol. 2015; 3: 8Crossref PubMed Google Scholar].