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

Kell DB, Oliver SG - Front Pharmacol (2014)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: School of Chemistry, The University of Manchester Manchester, UK ; Manchester Institute of Biotechnology, The University of Manchester Manchester, UK.

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.

No MeSH data available.


Related in: MedlinePlus

A “mind map” (Buzan, 2002) summarizing the structure and contents of this paper. To follow this, start at the top and read clockwise.
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Figure 1: A “mind map” (Buzan, 2002) summarizing the structure and contents of this paper. To follow this, start at the top and read clockwise.

Mentions: First, we might usefully establish (or, more accurately, restate) what our views are. The abstract of the Smith article (Smith et al., 2014) (“Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible”) recognizes that we imply a dominant role for transporter-mediated uptake of drugs into cells (note the titles of Dobson and Kell, 2008; Dobson et al., 2009a; Kell and Dobson, 2009; Kell et al., 2011, 2013). We do not assert that carrier-mediated transport is the only means by which drugs and other xenobiotics gain access to cells, nor do we seek to invalidate passive lipoidal diffusion as an alternate mechanism. Thus, we start by explaining, from a Popperian standpoint, why we do not seek to “invalidate” bilayer lipoidal diffusion. Figure 1 provides an overview of this article in the form of a mind map (Buzan, 2002).


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

Kell DB, Oliver SG - Front Pharmacol (2014)

A “mind map” (Buzan, 2002) summarizing the structure and contents of this paper. To follow this, start at the top and read clockwise.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215795&req=5

Figure 1: A “mind map” (Buzan, 2002) summarizing the structure and contents of this paper. To follow this, start at the top and read clockwise.
Mentions: First, we might usefully establish (or, more accurately, restate) what our views are. The abstract of the Smith article (Smith et al., 2014) (“Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible”) recognizes that we imply a dominant role for transporter-mediated uptake of drugs into cells (note the titles of Dobson and Kell, 2008; Dobson et al., 2009a; Kell and Dobson, 2009; Kell et al., 2011, 2013). We do not assert that carrier-mediated transport is the only means by which drugs and other xenobiotics gain access to cells, nor do we seek to invalidate passive lipoidal diffusion as an alternate mechanism. Thus, we start by explaining, from a Popperian standpoint, why we do not seek to “invalidate” bilayer lipoidal diffusion. Figure 1 provides an overview of this article in the form of a mind map (Buzan, 2002).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: School of Chemistry, The University of Manchester Manchester, UK ; Manchester Institute of Biotechnology, The University of Manchester Manchester, UK.

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.

No MeSH data available.


Related in: MedlinePlus