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

Pharm Res. 1998 May;15(5):739-44. doi: 10.1023/a:1011923103938.

Abstract

Purpose: 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.

MeSH terms

  • Adrenergic beta-Antagonists / chemistry*
  • Binding Sites
  • Drug Carriers / chemistry
  • Hydrogen-Ion Concentration
  • Liposomes / chemistry*
  • Mathematics
  • Membrane Lipids / chemistry*
  • Phosphatidylinositols / chemistry*
  • Propranolol / chemistry*
  • Radiopharmaceuticals / chemistry*

Substances

  • Adrenergic beta-Antagonists
  • Drug Carriers
  • Liposomes
  • Membrane Lipids
  • Phosphatidylinositols
  • Radiopharmaceuticals
  • Propranolol