CHARACTERIZATION OF DISTRIBUTION BEHAVIOR OF 2-IMIDAZOLINES INTO MULTILAMELLAR LIPOSOMES

The distribution of 2-imidazolines in neutral dimyristoylphosphatidylcholine (DMPC) liposomes, in negatively charged liposomes containing dicetylphosphate (DCP) or phosphatidylserine (PS), and in positively charged liposomes containing stearylamine (STA), has been investigated. Electrophoretic mobilities of multilamellar liposomes have also been measured as a function of drug concentration. Apparent equilibrium partition coefficients (log K'(m)) increased as a function of the DCP or PS concentration in DMPC liposomes whereas log K'(m) decreased with STA concentration, except for lofexidine and clonidine. Similarly, the electrokinetic parameters increased in DMPC liposomes that exhibited a small, positive surface charge, decreased in DMPC/cholesterol/DCP (7:1:2 mole ratio) liposomes, and increased in DMPC/STA (3:1 mole ratio) liposomes, except for clonidine which showed a decrease, as a function of the 2-imidazoline concentration. Surface potential change (DELTA-psi-0) due to drug inclusion in the liposomes obtained from theoretical considerations exhibited a positive linear relationship with log K'(m). Values of DELTA-psi-0 were greater but less sensitive to log K'(m) in negatively charged than in neutral or positively charged liposomes at 1 mM drug concentration. Likewise, surface charge densities varied in the same order as the surface potentials as a function of log K'(m) of the 2-imidazolines, except for clonidine and lofexidine. These data indicate the relative importance of the membrane surface characteristics on the partitioning behavior, and also possibly the membrane transport behavior, of the 2-imidazoline drugs.