Uptake and transport of new antiasthmatic compounds by human intestinal Caco-2 cells: correlations with lipophilicity by biopartitioning chromatography

Purpose: To characterize the membrane permeability and identify the mechanism of membrane transport for ten new antiasthmatic compounds by means of a combination of an in vitro cell model and various lipophilicity parameters. Methods: Human intestinal Caco-2 cells were used to measure cellular uptake and bidirectional transport. Lipophilicity was determined by biopartitioning chromatography (BPC, i.e. immobilized artificial membrane (1 AM) and biopartitioning miceller chromatography (BMC)) (log k) and an n-octanol/water system (log D and Clog P), respectively. Results: The cellular accumulation of compounds was pH-dependent, temperature-independent and unsaturable. In addition, no directional preference was observed in the bidirectional transport. Single-variable regression using lipophilicity from BPC was acceptable for the analysis of Caco-2 cell data. Multivariable regression analysis demonstrated that introducing molecular size and nonpolar surface area significantly improved the correlation of lipophilicity with either uptake or transport by cells. Conclusions: The results suggested that the new antiasthmatic compounds have a high membrane permeability and cellular accumulation, implying a potential high bioavailability in future clinic studies. A regular pattern involving a good correlation with BPC lipophilicity was observed for Caco-2 uptake and transport results, suggesting that passive diffusion was the principal mechanism governing drug transport across the cell membrane.