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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

Transport reactions may be discriminated both by whether they are equilibrative or concentrative in nature (a thermodynamic property) and whether they involve solely any phospholipid bilayer that may be present or instead rely on specific transporters (a mechanistic assessment). It is important not to confuse the two.
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Figure 3: Transport reactions may be discriminated both by whether they are equilibrative or concentrative in nature (a thermodynamic property) and whether they involve solely any phospholipid bilayer that may be present or instead rely on specific transporters (a mechanistic assessment). It is important not to confuse the two.

Mentions: It is also important to recognize that thermodynamics (and any other state variables) cannot tell you about mechanism either. The “pH-partition theory” (Hogben et al., 1959), of which much is made (e.g., Smith et al., 2014), simply tells one that protonable molecules that can exist at a certain pH in both ionized and non-ionized forms, and that are mainly permeable in the uncharged form, will distribute themselves according to any existing transmembrane pH gradients. This is extremely well-known (and not a recent observation), and such distributions have indeed long been used to estimate such pH gradients (Waddell and Butler, 1959), including by us (Kell et al., 1978a,b; Sorgato et al., 1978). Osmotic swelling methods may also be used to estimate the nature (but not the pathway or mechanism) of the most strongly permeating species (Kell et al., 1981). However, again, it is important to recognize that while the absence of a concentration gradient may indicate “the passive diffusion nature of (a transport) process,” the absence of such a gradient does not permit one to conclude whether the transport is through a bilayer by lipoidal diffusion or is carrier-mediated. Thermodynamics can speak to whether a process is passive in nature (i.e., not energy coupled) but not to its molecular mechanism. These two aspects form the orthogonal axes of a “Boston matrix” (Figure 3).


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)

Transport reactions may be discriminated both by whether they are equilibrative or concentrative in nature (a thermodynamic property) and whether they involve solely any phospholipid bilayer that may be present or instead rely on specific transporters (a mechanistic assessment). It is important not to confuse the two.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Transport reactions may be discriminated both by whether they are equilibrative or concentrative in nature (a thermodynamic property) and whether they involve solely any phospholipid bilayer that may be present or instead rely on specific transporters (a mechanistic assessment). It is important not to confuse the two.
Mentions: It is also important to recognize that thermodynamics (and any other state variables) cannot tell you about mechanism either. The “pH-partition theory” (Hogben et al., 1959), of which much is made (e.g., Smith et al., 2014), simply tells one that protonable molecules that can exist at a certain pH in both ionized and non-ionized forms, and that are mainly permeable in the uncharged form, will distribute themselves according to any existing transmembrane pH gradients. This is extremely well-known (and not a recent observation), and such distributions have indeed long been used to estimate such pH gradients (Waddell and Butler, 1959), including by us (Kell et al., 1978a,b; Sorgato et al., 1978). Osmotic swelling methods may also be used to estimate the nature (but not the pathway or mechanism) of the most strongly permeating species (Kell et al., 1981). However, again, it is important to recognize that while the absence of a concentration gradient may indicate “the passive diffusion nature of (a transport) process,” the absence of such a gradient does not permit one to conclude whether the transport is through a bilayer by lipoidal diffusion or is carrier-mediated. Thermodynamics can speak to whether a process is passive in nature (i.e., not energy coupled) but not to its molecular mechanism. These two aspects form the orthogonal axes of a “Boston matrix” (Figure 3).

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