PURPOSE: This study explores factors influencing the interactions of positively charged drugs with liposomes using liposome electrokinetic chromatography (LEKC) for the development of LEKC as a rapid screening method for drug-membrane interactions. METHODS: Liposomes were prepared and the retention factors were measured for a series of basic drugs under a variety of buffer conditions, including various buffer types, concentrations, and ionic strengths as well as using different phospholipids and liposome compositions. LEKC retention is compared with octanol-water partitioning. RESULTS: The interaction of ionizable solutes with liposomes decreased with increasing ionic strength of the aqueous buffer. The type of buffer also influences positively charged drug partitioning into liposomes. Varying the surface charge on the liposomes by the selection of phospholipids influences the electrostatic interactions, causing an increase in retention with increasing percentages of anionic lipids in the membrane. Poor correlations are observed between LEKC retention and octanol-water partitioning. CONCLUSIONS: These studies demonstrate the overall buffer ionic strength at a given pH is more important than buffer type and concentration. The interaction of positively charged drugs with charged lipid bilayer membranes is selectively influenced by the pKa of the drug. Liposomes are more biologically relevant in vitro models for cell membranes than octanol, and LEKC provides a unique combination of advantages for rapid screening of drug-membrane interactions.
PURPOSE: This study explores factors influencing the interactions of positively charged drugs with liposomes using liposome electrokinetic chromatography (LEKC) for the development of LEKC as a rapid screening method for drug-membrane interactions. METHODS: Liposomes were prepared and the retention factors were measured for a series of basic drugs under a variety of buffer conditions, including various buffer types, concentrations, and ionic strengths as well as using different phospholipids and liposome compositions. LEKC retention is compared with octanol-water partitioning. RESULTS: The interaction of ionizable solutes with liposomes decreased with increasing ionic strength of the aqueous buffer. The type of buffer also influences positively charged drug partitioning into liposomes. Varying the surface charge on the liposomes by the selection of phospholipids influences the electrostatic interactions, causing an increase in retention with increasing percentages of anionic lipids in the membrane. Poor correlations are observed between LEKC retention and octanol-water partitioning. CONCLUSIONS: These studies demonstrate the overall buffer ionic strength at a given pH is more important than buffer type and concentration. The interaction of positively charged drugs with charged lipid bilayer membranes is selectively influenced by the pKa of the drug. Liposomes are more biologically relevant in vitro models for cell membranes than octanol, and LEKC provides a unique combination of advantages for rapid screening of drug-membrane interactions.