Towards the predictability of drug-lipid membrane interactions: the pH-dependent affinity of propanolol to phosphatidylinositol containing liposomes.
OBJECTIVE
Prediction of the pH-dependent affinity of (RS)-[3H]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)-[3H]propranolol than the neutral solute, i.e. the partition coefficient of the protonated base (Pi) is 17'430+/-1320, P of the neutral compound (Pn) is 3110+/-1650. In the PhC-liposome system Pi is 580+/-17, Pn 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 Pn and Pi 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.
Krämer
S D
SD
Biopharmacy, Department of Pharmacy, ETH Zürich, Switzerland.
Braun
A
A
Jakits-Deiser
C
C
Wunderli-Allenspach
H
H
D000319:Adrenergic beta-Antagonists / Q000737:chemistry*; D001665:Binding Sites; D004337:Drug Carriers / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000737:chemistry*; D008433:Mathematics; D008563:Membrane Lipids / Q000737:chemistry*; D010716:Phosphatidylinositols / Q000737:chemistry*; D011433:Propranolol / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000737:chemistry*
D000319:Adrenergic beta-Antagonists; D004337:Drug Carriers; D008081:Liposomes; D008563:Membrane Lipids; D010716:Phosphatidylinositols; D019275:Radiopharmaceuticals; D011433:Propranolol