CONCENTRATION-DEPENDENT BINDING OF THE CHIRAL BETA-BLOCKER OXPRENOLOL TO ISOELECTRIC OR NEGATIVELY CHARGED UNILAMELLAR VESICLES

Large unilamellar vesicles (LUVs) of different lipid compositions were used to study the type of binding of the beta-blocking cationic agent oxprenolol to the lipid matrix of biological membranes at a physiologic pH value of 7.4. When isoelectric membranes of pure egg lecithin or egg lecithin/cholesterol (7:3 mol/mol) were used, a linear relationship between membrane-bound and free oxprenolol indicated a constant molar partition coefficient of 54 or 44 between the liposomal and the aqueous phase over a wide concentration range of the drug up to 25 mM. This pointed to deep insertion of the drug molecules into the hydrophobic membrane interior. Drug binding to membranes of negatively charged phosphatidylserine from bovine brain was cooperative with a Hill coefficient h of 3.4 at concentrations below 0.5 mM and a molar ratio R(e) of bound drug per lipid of 1:10. Above drug concentrations of 2.5 mM and R(e) = 1:5, a constant molar partition coefficient of 33 could be estimated. R-oxprenolol or S-oxprenolol, as well as the racemic drug, showed no differences in membrane binding, even with egg lecithin LUVs containing 20 mol% of the negatively charged (2S, 4R)-N-(hexadecanoyl)-4-hydroxyproline, which has a pronounced chiral headgroup. Our results suggest that enantioselective interactions of the chiral oxprenolol with the chiral lipids of biological membranes can be excluded. Furthermore, surface adsorption of the drug is probable only on the negatively charged cytosolic side of biological plasma membranes, whereas on the isoelectric exterior the cationic drug is inserted deeply into the membrane.