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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 “Boston matrix” comparing the activities of drugs in terms of whether their molecular and/or their tissue targets are each either single or multiple.
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Figure 10: A “Boston matrix” comparing the activities of drugs in terms of whether their molecular and/or their tissue targets are each either single or multiple.

Mentions: Indeed, one can devise a 2 × 2 matrix of molecular vs. tissue targeting in drug development (Figure 10); however, its most important quadrant is presently missing (see Figure 10). Thus, the “magic bullet” is a phrase that was coined by Paul Ehrlich (Bosch and Rosich, 2008), initially with regard to anti-infectives, to describe a chemical that specifically inhibits a disease-causing target. Much of modern pharmacology relies precisely upon this principle, and many highly potent drugs have been developed (Strebhardt and Ullrich, 2008). However, most effective drugs are, in fact, active on multiple targets (e.g., Hopkins, 2008; Mestres and Gregori-Puigjané, 2009; Kell et al., 2013) and there is an increasing recognition (e.g., Boran and Iyengar, 2010; Metz and Hajduk, 2010; Xie et al., 2012; Jalencas and Mestres, 2013; Medina-Franco et al., 2013; Peters, 2013; Anighoro et al., 2014) as we move toward a network or systems pharmacology (e.g., Hopkins, 2008; Van Der Graaf and Benson, 2011; Cucurull-Sanchez et al., 2012; Rostami-Hodjegan, 2012; Waldman and Terzic, 2012; Bai and Abernethy, 2013; Csermely et al., 2013; Jenkins and Ma'ayan, 2013; Kell and Goodacre, 2014) that polypharmacology (one drug, multiple targets) is actually a desirable goal. While this can be achieved with combination therapies (multiple drugs, multiple targets) (e.g., Borisy et al., 2003; Zimmermann et al., 2007; Lehár et al., 2008), an advantage of polypharmacology is that the pharmacokinetics of a single agent are considerably simpler. However, with regard to tissue targeting, the “magic bullet” is more like a “magic blunderbuss” in that the drug can, in principle, bind to its targets in whichever tissue they are found so that it is largely unselective, and this is also true for agents exhibiting polypharmacology. This is obviously particularly undesirable for cytotoxic drugs such as anti-cancer agents, and leads to many examples of unwanted toxicity. By including tissue targeting as an explicit goal, much lower amounts of active drug can be given, thereby improving their therapeutic index massively. The starting point for achieving this is indeed the recognition that drugs enter cells more or less solely by hitchhiking on transporters normally involved in the transport of intermediary metabolites, rather than by diffusing indiscriminately through any and every phospholipid bilayer. A striking example comes from the work of Pfefferkorn and colleagues, who noted a value of 250,000 for the hepatocyte:myocyte ratio of a particular transporter-targeted drug (Pfefferkorn et al., 2011). It is not obvious how any view of a significant bilayer transport occurring (as in BDII) can sensibly account for this without ad hoc extra hypotheses, whereas the view that any “background” lipoidal bilayer transport is negligible finds it very easy to do so.


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 “Boston matrix” comparing the activities of drugs in terms of whether their molecular and/or their tissue targets are each either single or multiple.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 10: A “Boston matrix” comparing the activities of drugs in terms of whether their molecular and/or their tissue targets are each either single or multiple.
Mentions: Indeed, one can devise a 2 × 2 matrix of molecular vs. tissue targeting in drug development (Figure 10); however, its most important quadrant is presently missing (see Figure 10). Thus, the “magic bullet” is a phrase that was coined by Paul Ehrlich (Bosch and Rosich, 2008), initially with regard to anti-infectives, to describe a chemical that specifically inhibits a disease-causing target. Much of modern pharmacology relies precisely upon this principle, and many highly potent drugs have been developed (Strebhardt and Ullrich, 2008). However, most effective drugs are, in fact, active on multiple targets (e.g., Hopkins, 2008; Mestres and Gregori-Puigjané, 2009; Kell et al., 2013) and there is an increasing recognition (e.g., Boran and Iyengar, 2010; Metz and Hajduk, 2010; Xie et al., 2012; Jalencas and Mestres, 2013; Medina-Franco et al., 2013; Peters, 2013; Anighoro et al., 2014) as we move toward a network or systems pharmacology (e.g., Hopkins, 2008; Van Der Graaf and Benson, 2011; Cucurull-Sanchez et al., 2012; Rostami-Hodjegan, 2012; Waldman and Terzic, 2012; Bai and Abernethy, 2013; Csermely et al., 2013; Jenkins and Ma'ayan, 2013; Kell and Goodacre, 2014) that polypharmacology (one drug, multiple targets) is actually a desirable goal. While this can be achieved with combination therapies (multiple drugs, multiple targets) (e.g., Borisy et al., 2003; Zimmermann et al., 2007; Lehár et al., 2008), an advantage of polypharmacology is that the pharmacokinetics of a single agent are considerably simpler. However, with regard to tissue targeting, the “magic bullet” is more like a “magic blunderbuss” in that the drug can, in principle, bind to its targets in whichever tissue they are found so that it is largely unselective, and this is also true for agents exhibiting polypharmacology. This is obviously particularly undesirable for cytotoxic drugs such as anti-cancer agents, and leads to many examples of unwanted toxicity. By including tissue targeting as an explicit goal, much lower amounts of active drug can be given, thereby improving their therapeutic index massively. The starting point for achieving this is indeed the recognition that drugs enter cells more or less solely by hitchhiking on transporters normally involved in the transport of intermediary metabolites, rather than by diffusing indiscriminately through any and every phospholipid bilayer. A striking example comes from the work of Pfefferkorn and colleagues, who noted a value of 250,000 for the hepatocyte:myocyte ratio of a particular transporter-targeted drug (Pfefferkorn et al., 2011). It is not obvious how any view of a significant bilayer transport occurring (as in BDII) can sensibly account for this without ad hoc extra hypotheses, whereas the view that any “background” lipoidal bilayer transport is negligible finds it very easy to do so.

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