FREE FATTY-ACIDS CAUSE PH-DEPENDENT CHANGES IN DRUG-LIPID MEMBRANE INTERACTIONS AROUND PHYSIOLOGICAL PH

Purpose. The influence of oleic acid (OA) and phosphatidylethanolamine (PhE) as membrane constituents on the partition behavior of (RS)-[H-3 ]propranolol between unilamellar liposomes and buffer was studied as a function of pH. Methods. Partition studies were performed by means of equilibrium dialysis at 37 degrees C over a broad pH range at a molar propranolol to lipid ratio in the membrane of 10(-6). Results. As com pared to the standard phosphatidylcholine (PhC)-liposome/buffer partit ion system PhE and OA have an enhancing effect on the apparent partiti on coefficient (D) of (RS)-[H-3]propranolol between pH 6 and 11. Data analysis with Henderson-Hasselbalch equations revealed that the neutra l propranolol has a higher affinity to membranes containing net neutra l charged PhE than to pure PhC-liposomes. Net negatively charged PhE s eems to have no significant influence on the partitioning. Deprotonate d OA caused an increase in the true partition coefficient (P) of the p rotonated propranolol. Neutral OA showed no influence on the partition ing. From the fit D vs pH curves and from zeta potential measurements of the liposomes the intrinsic pK(a) values of the membranous lipids w ere calculated as 7.5 to 7.8 for OA and 9.7 to 9.8 for PhE. Conclusion s. Since the pK(a) of membranous OA is close to the physiological pH a nd D depends on the ionisation state of OA, small pH changes around th e physiological pH may cause large differences in drug-lipid membrane interactions.