The apparent permeabilities of Caco-2 cells to marketed drugs: Magnitude, and independence fromboth biophysical properties and endogenite similarities

Abstract

We bring together fifteen, nonredundant, tabulated collections (amounting to 696 separate measurements) of the apparent permeability (Papp) of Caco-2 cellsto 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 transportermediated only. While these values are outliers, all values, and especially the comparatively low values normally observed, are entirely consistent with transporteronly 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 amultiplicity of transporters of comparatively weak specificity.