OBJECTIVE The influence of oleic acid (OA) and phosphatidylethanolamine (PhE) as membrane constituents on the partition behavior of (RS)-[3H]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 compared to the standard phosphatidylcholine (PhC)-liposome/buffer partition system PhE and OA have an enhancing effect on the apparent partition coefficient (D) of (RS)-[3H]propranolol between pH 6 and 11. Data analysis with Henderson-Hasselbalch equations revealed that the neutral propranolol has a higher affinity to membranes containing net neutral charged PhE than to pure PhC-liposomes. Net negatively charged PhE seems to have no significant influence on the partitioning. Deprotonated OA caused an increase in the true partition coefficient (P) of the protonated propranolol. Neutral OA showed no influence on the partitioning. From the fit D vs pH curves and from zeta potential measurements of the liposomes the intrinsic pKa values of the membranous lipids were calculated as 7.5 to 7.8 for OA and 9.7 to 9.8 for PhE. CONCLUSIONS Since the pKa of membranous OA is close to the physiological pH and D depends on the ionisation state of OA, small pH changes around the physiological pH may cause large differences in drug-lipid membrane interactions.