How do molecules get into cells…?…the continuing debate


Prompted by a number of recent comments in meetings and blogs, although the paper came out last year it is worth highlighting again the strongly held and opposing opinions on this topic.

If you pick up Drug Discovery Today from 2011, and read the Kell and Dobson article, you would be forgiven for thinking that you had missed a significant development in the understanding of diffusion into cells, and immediately start disregarding all the passive permeability data you’re generating.  Essentially, the argument in this paper, forcefully made and apparently with no clear challenge or comment during review & revision, is that passive diffusion plays no significant contribution to the entry of molecules into cells.  Instead, all drugs are actively transported by a diverse range of transporters – some know and some yet to be identified as illustrated by figure from paper below:

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This paper is at pains to refute an article in Drug Discovery Reviews the previous year discussing the co-existence of passive and active transport mechanisms.  The argument is based on the observation that when comparing the rates of drug transport in natural versus artificial membranes, there are discrepancies of over 100x, with the natural membranes demonstrating higher permeability.  The paper very appropriately points out the pitfalls of blindly using Caco-2 and/or MDCK systems and highlights numerous examples of drugs which don’t fit to the widely held views.

All these points were strongly (and convincingly) made, and some have read this paper and associated references, and taken all the points strongly to heart.

However, the co-existers rose up and fought back in the same journal, publishing an article the following year which is essentially a rebuttal of all the Kell and Dobson claims and a reassertion of the 2010 DDR paper.  In particular, it makes a strong re-assertion that passive diffusion is the major mechanism for blood-brain barrier permeation of lipophilic small molecules (Figure below from article; ref 31 = Tsinman, Pharm Res, 2011, 337).

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These arguments look reasoned and balanced, and importantly are based on considerable data. The door is still open to the presence of many other active transport processes, as well as to the approximate nature of current permeability screening assays, however a complete disregard of passive diffusion appears premature at best.

These papers have been already well covered by the excellent critique by Derek Lowe, however, the lack of awareness across some of our community of the existence of this debate and the uncompromising nature of the language in both papers circulating today (and the fun of seeing groups slogging it out over the pages of Drug Discovery Today) warranted a second airing…

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