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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 set of circumstances in which two otherwise identical organs, that take up the same total amount of a drug and may have indistinguishable PK/PD, nevertheless display entirely different behaviors because of the intercellular heterogeneity. Organ (A) may display favorable efficacy and toxicity profiles, while in organ (B) shows both a lack of efficacy (in at least part of the organ) and toxicity (in another part). Note that the total amount of tissue is the same in (A,B). Such phenomena may well underlie the two most common causes of attrition (Cook et al., 2014).
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Figure 9: A set of circumstances in which two otherwise identical organs, that take up the same total amount of a drug and may have indistinguishable PK/PD, nevertheless display entirely different behaviors because of the intercellular heterogeneity. Organ (A) may display favorable efficacy and toxicity profiles, while in organ (B) shows both a lack of efficacy (in at least part of the organ) and toxicity (in another part). Note that the total amount of tissue is the same in (A,B). Such phenomena may well underlie the two most common causes of attrition (Cook et al., 2014).

Mentions: Surprisingly few good data on this are available in the open literature, though in some cases one can see that the variation in concentration of a drug in different tissues (e.g., as measured by tissue:plasma ratio) can be massive (e.g., Miraglia et al., 2010; Oballa et al., 2011; Pagliarusco et al., 2011; Pfefferkorn et al., 2012). Note that when these kinds of measurements are made directly there is a highly heterogeneous distribution of drugs between different cells in the same tissue (e.g., Khatib-Shahidi et al., 2006; Cornett et al., 2008; Nilsson et al., 2010; Römpp et al., 2010, 2011; Castellino et al., 2011; Marko-Varga et al., 2011, 2012; Ait-Belkacem et al., 2012; Shahidi-Latham et al., 2012; El-Mashtoly et al., 2014; Gessel et al., 2014). The PBIN theory explains this straightforwardly in terms of the heterogeneous distribution of transporters, which is both well-known and measurable [see e.g., (http://proteinatlas.org/) (Persson et al., 2006; Pontén et al., 2008)]. A consequence of this highly heterogeneous distribution (Figure 9) is that one can find or predict circumstances in which, while the gross PK/PD of a drug's interactions at the level of an organ may not change, the heterogeneous distribution of a drug that might otherwise be efficacious and non-toxic means that it is simultaneously both non-efficacious and toxic (the two main causes of attrition in drug development; Arrowsmith, 2011; Hann, 2011; Arrowsmith and Miller, 2013; Cook et al., 2014).


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 set of circumstances in which two otherwise identical organs, that take up the same total amount of a drug and may have indistinguishable PK/PD, nevertheless display entirely different behaviors because of the intercellular heterogeneity. Organ (A) may display favorable efficacy and toxicity profiles, while in organ (B) shows both a lack of efficacy (in at least part of the organ) and toxicity (in another part). Note that the total amount of tissue is the same in (A,B). Such phenomena may well underlie the two most common causes of attrition (Cook et al., 2014).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: A set of circumstances in which two otherwise identical organs, that take up the same total amount of a drug and may have indistinguishable PK/PD, nevertheless display entirely different behaviors because of the intercellular heterogeneity. Organ (A) may display favorable efficacy and toxicity profiles, while in organ (B) shows both a lack of efficacy (in at least part of the organ) and toxicity (in another part). Note that the total amount of tissue is the same in (A,B). Such phenomena may well underlie the two most common causes of attrition (Cook et al., 2014).
Mentions: Surprisingly few good data on this are available in the open literature, though in some cases one can see that the variation in concentration of a drug in different tissues (e.g., as measured by tissue:plasma ratio) can be massive (e.g., Miraglia et al., 2010; Oballa et al., 2011; Pagliarusco et al., 2011; Pfefferkorn et al., 2012). Note that when these kinds of measurements are made directly there is a highly heterogeneous distribution of drugs between different cells in the same tissue (e.g., Khatib-Shahidi et al., 2006; Cornett et al., 2008; Nilsson et al., 2010; Römpp et al., 2010, 2011; Castellino et al., 2011; Marko-Varga et al., 2011, 2012; Ait-Belkacem et al., 2012; Shahidi-Latham et al., 2012; El-Mashtoly et al., 2014; Gessel et al., 2014). The PBIN theory explains this straightforwardly in terms of the heterogeneous distribution of transporters, which is both well-known and measurable [see e.g., (http://proteinatlas.org/) (Persson et al., 2006; Pontén et al., 2008)]. A consequence of this highly heterogeneous distribution (Figure 9) is that one can find or predict circumstances in which, while the gross PK/PD of a drug's interactions at the level of an organ may not change, the heterogeneous distribution of a drug that might otherwise be efficacious and non-toxic means that it is simultaneously both non-efficacious and toxic (the two main causes of attrition in drug development; Arrowsmith, 2011; Hann, 2011; Arrowsmith and Miller, 2013; Cook et al., 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