Kinetics of lipid bilayer permeation of a series of ionisable drugs and their correlation with human transporter-independent intestinal permeability

Abstract

For low molecular weight drugs, lipid bilayer permeation is considered the major route for in vivo cell barrier passage. We recently introduced a fluorescence assay with liposomes to determine permeation kinetics of ionisable compounds across the lipid bilayer by monitoring drug-induced pH changes inside the liposomes. Here, we determined the permeability coefficients (P_FLipP, FLipP for "Fluorescence Liposomal Permeability") across 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers of 35 ionisable drugs at pH6.0 and compared them to available in vivo human jejunal permeability (P_eff) data. P_FLipP values were furthermore compared with published Caco-2 cell permeability coefficients (P_Caco-2), permeability coefficients determined with the parallel artificial membrane permeability assay (PAMPA) and with log D (pH6.0). The log P_FLipP, corrected for predicted para-cellular diffusion, and log P_Caco-2 correlated best with log P_eff, with similar adjusted R² (0.75 and 0.74, n=12). Our results suggest that transporter-independent intestinal drug absorption is predictable from liposomal permeability.

Keywords: Caco-2; FLipP; Fluorescence; Intestinal absorption; Liposomes; Permeability.