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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

Relationships between uptake of drugs into erythrocyte and their log P, (A) as redrawn from the plot in Figure 4 of Smith et al. (2014), along with their best-fit straight line (logKe/p,u = −0.013 + 0.22 logPoct), r2 = 0.59, and (B) the same data plotted with the ordinate encoded linearly, using the same colored symbols as in Figure 4A. We do not try to fit a straight line through the left-hand 32 drugs and the right-hand 6 drugs.
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Figure 4: Relationships between uptake of drugs into erythrocyte and their log P, (A) as redrawn from the plot in Figure 4 of Smith et al. (2014), along with their best-fit straight line (logKe/p,u = −0.013 + 0.22 logPoct), r2 = 0.59, and (B) the same data plotted with the ordinate encoded linearly, using the same colored symbols as in Figure 4A. We do not try to fit a straight line through the left-hand 32 drugs and the right-hand 6 drugs.

Mentions: According to Smith et al. (2014), their “Figure 4 shows that the uptake of drugs into human red blood cells significantly correlates with log P.” We reproduce their Figure 4 as our Figure 4A below. The ordinate data are in fact taken from a review by Hinderling (1997) and an earlier monograph. What is plotted on the ordinate, however, is not the uptake (or partitioning) but (for whatever reason) the logarithm of the uptake/partitioning. When we plot erythrocyte uptake against the ability to partition (and not its logarithm) into octanol (Figure 4B), we find that there is, in fact, little correlation. This is unsurprising given that the slope of Figure 4 in Smith et al. (2014) in log-log space is just 0.22 and that some pairs of data points are more than two orders of magnitude away from others with a similar ordinate or abscissa value. We would repeat our advice (Kell et al., 2011) against putting one's faith in log-log plots when their slope is far from unity. Other examples of a lack of correlation of uptake with log P/log D are given below. [Phenomena that do correlate with log P, however, include protein binding (Hughes et al., 2008), drug promiscuity (Azzaoui et al., 2007; Leeson and Springthorpe, 2007; Hann, 2011; Kell et al., 2013) and toxicity (Hughes et al., 2008; Hann, 2011)].


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)

Relationships between uptake of drugs into erythrocyte and their log P, (A) as redrawn from the plot in Figure 4 of Smith et al. (2014), along with their best-fit straight line (logKe/p,u = −0.013 + 0.22 logPoct), r2 = 0.59, and (B) the same data plotted with the ordinate encoded linearly, using the same colored symbols as in Figure 4A. We do not try to fit a straight line through the left-hand 32 drugs and the right-hand 6 drugs.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Relationships between uptake of drugs into erythrocyte and their log P, (A) as redrawn from the plot in Figure 4 of Smith et al. (2014), along with their best-fit straight line (logKe/p,u = −0.013 + 0.22 logPoct), r2 = 0.59, and (B) the same data plotted with the ordinate encoded linearly, using the same colored symbols as in Figure 4A. We do not try to fit a straight line through the left-hand 32 drugs and the right-hand 6 drugs.
Mentions: According to Smith et al. (2014), their “Figure 4 shows that the uptake of drugs into human red blood cells significantly correlates with log P.” We reproduce their Figure 4 as our Figure 4A below. The ordinate data are in fact taken from a review by Hinderling (1997) and an earlier monograph. What is plotted on the ordinate, however, is not the uptake (or partitioning) but (for whatever reason) the logarithm of the uptake/partitioning. When we plot erythrocyte uptake against the ability to partition (and not its logarithm) into octanol (Figure 4B), we find that there is, in fact, little correlation. This is unsurprising given that the slope of Figure 4 in Smith et al. (2014) in log-log space is just 0.22 and that some pairs of data points are more than two orders of magnitude away from others with a similar ordinate or abscissa value. We would repeat our advice (Kell et al., 2011) against putting one's faith in log-log plots when their slope is far from unity. Other examples of a lack of correlation of uptake with log P/log D are given below. [Phenomena that do correlate with log P, however, include protein binding (Hughes et al., 2008), drug promiscuity (Azzaoui et al., 2007; Leeson and Springthorpe, 2007; Hann, 2011; Kell et al., 2013) and toxicity (Hughes et al., 2008; Hann, 2011)].

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