How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

Abstract

One approach to experimental science involves creating hypotheses, then testing them by varying one or more independent variables, and assessing the effects of this variation on the processes of interest. We use this strategy to compare the intellectual status and available evidence for two models or views of mechanisms of transmembrane drug transport into intact biological cells. One (BDII) asserts that lipoidal phospholipid Bilayer Diffusion Is Important, while a second (PBIN) proposes that in normal intact cells Phospholipid Bilayer diffusion Is Negligible (i.e., may be neglected quantitatively), because evolution selected against it, and with transmembrane drug transport being effected by genetically encoded proteinaceous carriers or pores, whose “natural” biological roles, and substrates are based in intermediary metabolism. Despite a recent review elsewhere, we can find no evidence able to support BDII as we can find no experiments in intact cells in which phospholipid bilayer diffusion was either varied independently or measured directly (although there are many papers where it was inferred by seeing a covariation of other dependent variables). By contrast, we find an abundance of evidence showing cases in which changes in the activities of named and genetically identified transporters led to measurable changes in the rate or extent of drug uptake. PBIN also has considerable predictive power, and accounts readily for the large differences in drug uptake between tissues, cells and species, in accounting for the metabolite-likeness of marketed drugs, in pharmacogenomics, and in providing a straightforward explanation for the late-stage appearance of toxicity and of lack of efficacy during drug discovery programmes despite macroscopically adequate pharmacokinetics. Consequently, the view that Phospholipid Bilayer diffusion Is Negligible (PBIN) provides a starting hypothesis for assessing cellular drug uptake that is much better supported by the available evidence, and is both more productive and more predictive.

Master and servant: Regulation of auxin transporters by FKBPs and cyclophilins

“…As to our knowledge, whether this is completely so has never been proven experimentally. In this context it is worth mentioning that drug leakage into cells by lipophilic diffusion versus hitchhiking of transporters is currently highly debated in the animal literature [15].…”

“…The Arabidopsis genome encodes for 23 FKBP genes compared to Saccharomyces cerevisiae (4), Caenorhabditis elegans (8) and Homo sapiens (15). Arabidopsis has seven multi-domain FKBPs and 16 single-domain FKBPs [55].…”

Control of metabolite efflux in microbial cell factories: current advances and future prospects

“…Although our focus here is on microorganisms (and see [13]), the situation is also acute for mammalian transporters, as these underpin the distributions of xenobiotic pharmaceutical drugs within and between cells [8,[14][15][16][17][18][19][20].…”

“…When the mechanism involves a transporter it is properly known as 'facilitated diffusion'. Since these two uses of 'passive' are often conflated, and consequently cause much unnecessary confusion, we recommend that the term 'passive' is simply dropped in the context of transporters [8]. Figure 2.…”

A Call for Systematic Research on Solute Carriers

“…In many respects, the integrity of the membranes represents as critical an element to cellular individuality as does the preservation and transmission of genetic information (Schrum et al, 2010). The protein components of cell membranes import and export most of the chemical matter essential for life, including water, ions, gases, nutrients, vitamins, cofactors, and many drugs (Kell et al, 2011;Kell and Oliver, 2014;Lin et al, 2015). Therefore, regulation of small-molecule transport across membranes is key to a cell's internal physiology and is the gatekeeper to its interface with the environment (Nigam, 2015).…”