THE BARRIER DOMAIN FOR SOLUTE PERMEATION VARIES WITH LIPID BILAYER PHASE-STRUCTURE

The chemical selectivities of the transport barriers in lipid bilayers varying in composition and phase structure (gel-phase DPPC and DHPC b ilayers and liquid-crystalline DPPC/CHOL/50:50 mol% bilayers) have bee n investigated by determining functional group contributions to transp ort of a series of alpha-substituted p-toluic acid analogs obtained in vesicle efflux experiments. Linear free energy relationships are esta blished between the free energies of transfer for this series of compo unds from water to the barrier domain and corresponding values for the ir transfer from water into six model bulk solvents (hexadecane, hexad ecene, decadiene, chlorobutane, butyl ether, and octanol) determined i n partitioning experiments to compare the barrier microenvironment to that in these model solvents. The barrier microenvironment in all bila yers studied is substantially more hydrophobic than octanol, thus esta blishing the location of the barrier beyond the hydrated headgroup int erfacial region, as the interface is expected to be more hydrophilic t han octanol. The chemical nature of the barrier domain microenvironmen t varies with bilayer phase structure. The barrier regions in non-inte rdigitated DPPC and interdigitated DHPC gel-phase bilayers exhibit som e degree of hydrogen-bond acceptor capacity as may occur if these doma ins lie in the vicinity of the ester/ether linkages between the headgr oups and the acyl chains. Intercalation of 50 mol% cholesterol into DP PC bilayers, which induces a phase transition to a liquid-crystalline phase, substantially increases the apparent barrier domain hydrophobic ity relative to gel-phase bilayers to a nonhydrogen bonding, hydrocarb onlike environment resembling hexadecene. This result, combined with s imilar observations in liquid-crystalline egg-PC bilayers (J. Pharm. S ci. (1994), 83:1511-1518), supports the notion that the transition fro m the gel-phase to liquid-crystalline phase shifts the barrier domain further into the bilayer interior (i.e., deeper within the ordered cha in region).