How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphar.2014.00231/full |
| _version_ | 1819111822709489664 |
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| author | Douglas Bruce Kell Stephen George Oliver |
| author_facet | Douglas Bruce Kell Stephen George Oliver |
| author_sort | Douglas Bruce Kell |
| collection | DOAJ |
| description | 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, |
| first_indexed | 2024-12-22T04:03:43Z |
| format | Article |
| id | doaj.art-90517f1743dd4f02a30081c419cdf3db |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-22T04:03:43Z |
| publishDate | 2014-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-90517f1743dd4f02a30081c419cdf3db2022-12-21T18:39:41ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122014-10-01510.3389/fphar.2014.00231113250How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusionDouglas Bruce Kell0Stephen George Oliver1The University of ManchesterThe University of CambridgeOne 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,http://journal.frontiersin.org/Journal/10.3389/fphar.2014.00231/fullpharmacogenomicsdrug transportersadverse drug reactionsmolecular dynamicstissue specificitySpecies Specificity |
| spellingShingle | Douglas Bruce Kell Stephen George Oliver How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion Frontiers in Pharmacology pharmacogenomics drug transporters adverse drug reactions molecular dynamics tissue specificity Species Specificity |
| title | How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion |
| title_full | How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion |
| title_fullStr | How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion |
| title_full_unstemmed | How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion |
| title_short | How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion |
| title_sort | how drugs get into cells tested and testable predictions to help discriminate between transporter mediated uptake and lipoidal bilayer diffusion |
| topic | pharmacogenomics drug transporters adverse drug reactions molecular dynamics tissue specificity Species Specificity |
| url | http://journal.frontiersin.org/Journal/10.3389/fphar.2014.00231/full |
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