Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only

All cells necessarily contain tens, if not hundreds, of carriers for nutrients and intermediary metabolites, and the human genome codes for more than 1000 carriers of various kinds. Here, we illustrate using a typical literature example the widespread but erroneous nature of the assumption that the ‘background’ or ‘passive’ permeability to drugs occurs in the absence of carriers. Comparison of the rate of drug transport in natural versus artificial membranes shows discrepancies in absolute magnitudes of 100-fold or more, with the carrier-containing cells showing the greater permeability. Expression profiling data show exactly which carriers are expressed in which tissues. The recognition that drugs necessarily require carriers for uptake into cells provides many opportunities for improving the effectiveness of the drug discovery process.

Introduction

There is considerable and increasing evidence that drugs get into cells more or less solely by hitchhiking on carriers normally used for the transport of nutrients and intermediary metabolites 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38. This said, one can find reviews (e.g. 39, 40) that play up the importance of a different cellular route of uptake of pharmaceutical drugs considered to be occurring by simple diffusion through the hydrophobic lipid bilayer portions of biological membranes (and thereby strongly dependent on lipophilicity). Such works also lay stress on studies using artificial membrane systems lacking any proteins, although, as we shall see below, the relevance of such systems (given that the protein:lipid ratio in biological membranes is 1:1–3:1) is at best questionable.

A particular example of a detailed review seeking to provide evidence for the ‘mainly bilayer’ mode of transport is a recent article by Sugano et al. [40], which sought to show that the well-established carrier-mediated transport effecting the cellular uptake of pharmaceutical drugs 1, 10, 13, 14, 17 nevertheless coexists with a so-called ‘passive’ uptake of comparable magnitude, mediated via the bilayer portions of biological membranes. (In the literature, ‘passive’ normally means non-concentrative, including facilitated diffusion via a carrier; however, where appropriate in this article, we adopt the usage of Sugano et al. [40] to imply, as in their Fig. 1 and Box 3, transport through a bilayer portion of a phospholipid cell membrane.) That review [40] served to highlight some of the reasoning used by those who believe in the importance of trans-bilayer transport and the evidence that is purported to underpin it; therefore, the article is helpful in highlighting where the intellectual issues lie. Consequently, we focus several strands of our argument here on those detailed by Sugano et al. [40].

At the outset, one should comment that, despite the considerable literature surveyed [40], the title assertion of [40] [a coexistence of such ‘passive’ and carrier-mediated processes in (cellular) drug transport] fails, because it is simply that (an assertion). Specifically, the authors (and much of the literature they cite) make (and repeat) the same assumption throughout, which is that anything that is not taken up using a carrier that they know about therefore goes through the presumed bilayer portion of the relevant biological membrane, rather than through carriers they either do not know about (in biological membranes) or through transient aqueous pores that occur widely in artificial lipid membranes but not in real biological membranes. When these features are taken into account, the actual requirement, and any evidence, for such ‘passive’ permeation disappears. Although it is possible that such trans-bilayer ‘passive’ permeation occurs at meaningful rates, there appears to be no compelling evidence as yet that any pharmaceutical drug crosses real cell membranes by passing through the hydrophobic portion of a phospholipid bilayer. However, as noted above, [40] does provide an excellent basis to help focus on some key issues. We therefore compare the assumptions made by Sugano et al. (Fig. 1a; redrawn from Fig. 1 of [40]) with the mechanisms that they did not include (Fig. 1b) and which, in our view, are dominant.