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

Steve O'Hagan, Douglas B Kell

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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 P app 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 P app 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.
    Original languageEnglish
    JournalPeerJ
    Volume3
    DOIs
    Publication statusPublished - 17 Nov 2015

    Keywords

    • Caco-2 cells
    • Cheminformatics
    • Facilitated diffusion/transport
    • Mathematical models
    • Oral absorption
    • Permeability
    • Transcellular transport
    • Transporter-mediated uptake
    • Transporters

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