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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

The percentage of particular drug doses excreted in the urine for 350 of 351 “class 1” BDDCS drugs (Benet et al., 2011; one drug was excluded as it was too water soluble to measure) as a function of (A) the measured and (B) the calculated log P (c log P) (calculated using the RDKit software Landrum et al., 2011 and KNIME, Berthold et al., 2007; Mazanetz et al., 2012). Ordinate data are taken from Table 1 of Benet et al. (2011).
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Figure 8: The percentage of particular drug doses excreted in the urine for 350 of 351 “class 1” BDDCS drugs (Benet et al., 2011; one drug was excluded as it was too water soluble to measure) as a function of (A) the measured and (B) the calculated log P (c log P) (calculated using the RDKit software Landrum et al., 2011 and KNIME, Berthold et al., 2007; Mazanetz et al., 2012). Ordinate data are taken from Table 1 of Benet et al. (2011).

Mentions: According to the Biopharmaceutics Drug Disposition Classification System (BDDCS) (Benet et al., 2008, 2011; Benet, 2010), which bears at least some similarities to the BCS, the disposition of drugs represented in its class 1 (high permeability and high metabolism) category is considered to be completely unaffected by the presence of transporters in the gut and liver. At least two interpretations of this are possible (Estudante et al., 2013): (i) there are no transporters interacting with these drugs and all the transport is by lipoidal diffusion, or (ii) there are so many high-flux transporters that they simply do not provide a barrier to uptake. A surrogate for cellular uptake and metabolism in the BDDCS system is the extent to which drugs are excreted unchanged in the urine (low extent unchanged implying high metabolism, hence cellular uptake), and we have redrawn (Figure 8) plots of this against both measured and calculated log P values for 350 of the 351 BDDCS class 1 drugs tabulated (rather than being visualized) in Benet et al. (2011). It is obvious that the amount of drug excreted unchanged in the urine (and thus presumably its cellular permeability) can take almost any value whatever the value of log P, over an extremely wide range of values of log P. We have not chosen to fit a statistical line to either of these figures. Thus, we also suggest that it is useful if data that are supposed to support claims are made available in both tabular and graphical form, the latter with linear coordinates on both axes.


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)

The percentage of particular drug doses excreted in the urine for 350 of 351 “class 1” BDDCS drugs (Benet et al., 2011; one drug was excluded as it was too water soluble to measure) as a function of (A) the measured and (B) the calculated log P (c log P) (calculated using the RDKit software Landrum et al., 2011 and KNIME, Berthold et al., 2007; Mazanetz et al., 2012). Ordinate data are taken from Table 1 of Benet et al. (2011).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: The percentage of particular drug doses excreted in the urine for 350 of 351 “class 1” BDDCS drugs (Benet et al., 2011; one drug was excluded as it was too water soluble to measure) as a function of (A) the measured and (B) the calculated log P (c log P) (calculated using the RDKit software Landrum et al., 2011 and KNIME, Berthold et al., 2007; Mazanetz et al., 2012). Ordinate data are taken from Table 1 of Benet et al. (2011).
Mentions: According to the Biopharmaceutics Drug Disposition Classification System (BDDCS) (Benet et al., 2008, 2011; Benet, 2010), which bears at least some similarities to the BCS, the disposition of drugs represented in its class 1 (high permeability and high metabolism) category is considered to be completely unaffected by the presence of transporters in the gut and liver. At least two interpretations of this are possible (Estudante et al., 2013): (i) there are no transporters interacting with these drugs and all the transport is by lipoidal diffusion, or (ii) there are so many high-flux transporters that they simply do not provide a barrier to uptake. A surrogate for cellular uptake and metabolism in the BDDCS system is the extent to which drugs are excreted unchanged in the urine (low extent unchanged implying high metabolism, hence cellular uptake), and we have redrawn (Figure 8) plots of this against both measured and calculated log P values for 350 of the 351 BDDCS class 1 drugs tabulated (rather than being visualized) in Benet et al. (2011). It is obvious that the amount of drug excreted unchanged in the urine (and thus presumably its cellular permeability) can take almost any value whatever the value of log P, over an extremely wide range of values of log P. We have not chosen to fit a statistical line to either of these figures. Thus, we also suggest that it is useful if data that are supposed to support claims are made available in both tabular and graphical form, the latter with linear coordinates on both axes.

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