Towards the predictability of drug-lipid membrane interactions:: The pH-dependent affinity of propranolol to phosphatidylinositol containing liposomes

Purpose. Prediction of the pH-dependent affinity of (RS)-[H-3]propranolol to mixed phosphatidylcholine (PhC)/phosphatidylinositol(Phl) membranes from the partitioning in the single lipid liposome/buffer systems. Methods. Partition studies in liposome/buffer systems were performed by means of equilibrium dialysis at 37 degrees C between pH 2 and 11 at a molar propranolol to lipid ratio of 10(-6) to 10(-5) in the membrane. Results. The Phl membrane more strongly attracts the protonated (RS)-[H-3]propranolol than the neutral solute, i.e. the partition coefficient of the protonated base (P-i) is 17'430 +/- 1320, P of the neutral compound (P-n) is 3110 +/- 1650. In the PhC-liposome system P-i is 580 +/- 17, P-n 1860 +/- 20. The partition coefficients show an exponential dependence on the molar Phl fraction in mixed liposomes. The partitioning in mixed PhC/Phl membranes is predictable from P-n and P-i in the single lipid liposome systems. Conclusions. The negative charge of biological lipid membranes causes strong electrostatic interactions with positively charged solutes. This strong attraction is not predictable from the octanol/buffer partition system, but it is important regarding drug accumulation in the tissue and drug attraction by certain lipids in the vicinity of membrane proteins.