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]proprano lol to mixed phosphatidylcholine (PhC)/phosphatidylinositol(Phl) membr anes 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 membr ane. Results. The Phl membrane more strongly attracts the protonated ( RS)-[H-3]propranolol than the neutral solute, i.e. the partition coeff icient of the protonated base (P-i) is 17'430 +/- 1320, P of the neutr al 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 expone ntial dependence on the molar Phl fraction in mixed liposomes. The par titioning in mixed PhC/Phl membranes is predictable from P-n and P-i i n 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 predic table from the octanol/buffer partition system, but it is important re garding drug accumulation in the tissue and drug attraction by certain lipids in the vicinity of membrane proteins.