Affiliation:
1. School of Chemistry & The Manchester Institute of Biotechnology and Centre for Synthetic Biology of Fine and Speciality Chemicals (SYNBIOCHEM), The University of Manchester, Manchester, Lancs, United Kingdom
Abstract
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 medianPappvalue being some 16 ⋅ 10−6cm s−1. This value is considerably lower than those (1,310 and 230 ⋅ 10−6cm s−1) recently used in some simulations that purported to show thatPappvalues 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.
Funder
The Biotechnology and Biological Sciences Research Council
Centre for Synthetic Biology of Fine and Speciality Chemicals (SYNBIOCHEM)
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
42 articles.
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