Drug Absorption Principles

Cao, Xianhua; Yu, Lawrence X.; Sun, Duxin

doi:10.1007/978-0-387-72379-2_4

Cited by 16 publications

(8 citation statements)

References 45 publications

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“…(Dobson & Kell 2008;Kell 2013;Kell 2015;Kell et al 2013;Kell et al 2011;Kell & Oliver 2014)) that suggests that (in contrast to the general textbook belief, e.g. (Avdeef 2012;Cao et al 2006;Krogsgaard-Larsen et al 1996;van De Waterbeemd & Testa 2009)) small molecule drugs 'hitchhike' on the many protein transporters (Kell 2013;Kell & Goodacre 2014;Sahoo et al 2014;Thiele et al 2013) that are part of normal intermediary metabolism. These transporters may be identified via experiments where gene expression levels are manipulated systematically as independent variables (Giacomini et al 2010;Han et al 2015;Kell & Oliver 2014;Lanthaler et al 2011;Winter et al 2014).…”

Section: Introductionmentioning

confidence: 95%

The apparent permeabilities of Caco-2 cells to marketed drugs: magnitude, and independence from both biophysical properties and endogenite similarities

O’Hagan

Kell

2015

Preprint

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Abstract15 We bring together fifteen, nonredundant, tabulated collections (amounting to 696 separate 16 measurements) of the apparent permeability (P app ) of Caco-2 cells to marketed drugs. While in some 17 cases there are some significant interlaboratory disparities, most are quite minor. Most drugs are not 18 especially permeable through Caco-2 cells, with the median P app value being some 16 . 10 -6 cm.s -1 . This 19 value is considerably lower than those (1310 and 230 . 10 -6 cm.s -1 ) recently used in some recent 20 simulations that purported to show that P app values were too great to be transporter-mediated only. 21 While these values are outliers, all values, and especially the comparatively low values normally 22 observed, are entirely consistent with transporter-only mediated uptake, with no need to invoke 23 phospholipid bilayer diffusion. The apparent permeability of Caco-2 cells to marketed drugs is poorly 24 correlated with either simple biophysical properties, the extent of molecular similarity to endogenous 25 metabolites (endogenites), or any specific substructural properties. In particular, the octanol:water 26 partition coefficient, log P, shows negligible correlation with Caco-2 permeability. The data are best 27 explained on the basis that most drugs enter (and exit) Caco-2 cells via a multiplicity of transporters of 28 comparatively weak specificity.

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Section: Introductionmentioning

confidence: 95%

The apparent permeabilities of Caco-2 cells to marketed drugs: magnitude, and independence from both biophysical properties and endogenite similarities

O’Hagan

Kell

2015

Preprint

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show abstract

“…Understanding how this transport is effected remains a major challenge ( Kell & Oliver, 2014 ). We have brought together considerable published evidence (e.g., Dobson & Kell, 2008 ; Kell, 2013 ; Kell, 2015 ; Kell et al, 2013 ; Kell, Dobson & Oliver, 2011 ; Kell & Oliver, 2014 ) that suggests that (in contrast to the general textbook belief, e.g., Avdeef, 2012 ; Cao, Yu & Sun, 2006 ; Krogsgaard-Larsen, Liljefors & Madsen, 1996 ; Van De Waterbeemd & Testa, 2009 ) small molecule drugs ‘hitchhike’ on the many protein transporters ( Kell, 2013 ; Kell & Goodacre, 2014 ; Sahoo et al, 2014 ; Thiele et al, 2013 ) that are part of normal intermediary metabolism. These transporters may be identified via experiments where gene expression levels are manipulated systematically as independent variables ( César-Razquin et al, 2015 ; Giacomini et al, 2010 ; Han et al, 2015 ; Kell & Oliver, 2014 ; Lanthaler et al, 2011 ; Winter et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

The apparent permeabilities of Caco-2 cells to marketed drugs: magnitude, and independence from both biophysical properties and endogenite similarities

O’Hagan

Kell

2015

PeerJ

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We bring together fifteen, nonredundant, tabulated collections (amounting to 696 separate measurements) of the apparent permeability (Papp) of Caco-2 cells to marketed drugs. While in some cases there are some significant interlaboratory disparities, most are quite minor. Most drugs are not especially permeable through Caco-2 cells, with the median Papp value being some 16 ⋅ 10−6 cm s−1. This value is considerably lower than those (1,310 and 230 ⋅ 10−6 cm s−1) recently used in some simulations that purported to show that Papp values were too great to be transporter-mediated only. While these values are outliers, all values, and especially the comparatively low values normally observed, are entirely consistent with transporter-only mediated uptake, with no need to invoke phospholipid bilayer diffusion. The apparent permeability of Caco-2 cells to marketed drugs is poorly correlated with either simple biophysical properties, the extent of molecular similarity to endogenous metabolites (endogenites), or any specific substructural properties. In particular, the octanol:water partition coefficient, logP, shows negligible correlation with Caco-2 permeability. The data are best explained on the basis that most drugs enter (and exit) Caco-2 cells via a multiplicity of transporters of comparatively weak specificity.

show abstract

“…(Dobson & Kell 2008;Kell 2013;Kell 2015;Kell et al 2013;Kell et al 2011;Kell & Oliver 2014)) that suggests that (in contrast to the general textbook belief, e.g. (Avdeef 2012;Cao et al 2006;Krogsgaard-Larsen et al 1996;van De Waterbeemd & Testa 2009)) small molecule drugs 'hitchhike' on the many protein transporters (Kell 2013;Kell & Goodacre 2014;Sahoo et al 2014;Thiele et al 2013) that are part of normal intermediary metabolism. These transporters may be identified via experiments where gene expression levels are manipulated systematically as independent variables (César-Razquin et al 2015;Giacomini et al 2010;Han et al 2015;Kell & Oliver 2014;Lanthaler et al 2011;Winter et al 2014).…”

Section: Introductionmentioning

confidence: 95%

Peer Review #5 of "The apparent permeabilities of Caco-2 cells to marketed drugs: magnitude, and independence from both biophysical properties and endogenite similarities (v0.2)"

2015

View full text Add to dashboard Cite

We bring together fifteen, nonredundant, tabulated collections (amounting to 696 separate measurements) of the apparent permeability (P app) of Caco-2 cells to marketed drugs. While in some cases there are some significant interlaboratory disparities, most are quite minor. Most drugs are not especially permeable through Caco-2 cells, with the median Papp value being some 16. 10-6 cm.s-1. This value is considerably lower than those (1310 and 230. 10-6 cm.s-1) recently used in some simulations that purported to show that Papp values were too great to be transporter-mediated only. While these values are outliers, all values, and especially the comparatively low values normally observed, are entirely consistent with transporter-only mediated uptake, with no need to invoke phospholipid bilayer diffusion. The apparent permeability of Caco-2 cells to marketed drugs is poorly correlated with either simple biophysical properties, the extent of molecular similarity to endogenous metabolites (endogenites), or any specific substructural properties. In particular, the octanol:water partition coefficient, log P, shows negligible correlation with Caco-2 permeability. The data are best explained on the basis that most drugs enter (and exit) Caco-2 cells via a multiplicity of transporters of comparatively weak specificity.

show abstract

Drug Absorption Principles

Cited by 16 publications

References 45 publications

The apparent permeabilities of Caco-2 cells to marketed drugs: magnitude, and independence from both biophysical properties and endogenite similarities

The apparent permeabilities of Caco-2 cells to marketed drugs: magnitude, and independence from both biophysical properties and endogenite similarities

The apparent permeabilities of Caco-2 cells to marketed drugs: magnitude, and independence from both biophysical properties and endogenite similarities

Peer Review #5 of "The apparent permeabilities of Caco-2 cells to marketed drugs: magnitude, and independence from both biophysical properties and endogenite similarities (v0.2)"

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