Modifications in lipoprotein surface charge alter cyclosporine A association with low-density lipoproteins.
OBJECTIVE
The purpose of this study was to examine the influence of lipoprotein surface charge on the plasma distribution of cyclosporine A (CSA).


METHODS
Phosphatidylinositol (PI; 40 micromol) was administered intravenously to rabbits. Blood was removed 10 min after injection and plasma was retrieved. Radiolabeled CSA ([3H] CSA) at a concentration of 1000 ng/mL was incubated for 60 min at 37 degrees C in control and PI-treated rabbit plasma. After incubation, plasma was separated into its lipoprotein and lipoprotein-deficient plasma (LPDP) fractions by density gradient ultracentrifugation, and the percentage of [3H]CSA recovered in each fraction was determined by radioactivity. To determine lipoprotein surface charge within control and PI-treated plasma, the zeta potential of each lipoprotein fraction was measured. The effect of PI on lipoprotein surface charge was further confirmed by gel electrophoresis.


RESULTS
PI treatment caused low-density lipoprotein (LDL) fraction to migrate further on the agarose gel, indicative of an increased negative surface charge. Zeta potential analysis further showed that LDL particles had a surface potential of -11.4 +/- 1.9 mV and -17.4 +/- 3 mV in control and PI-treated groups, respectively. A greater percentage of [3H]CSA was recovered within the LDL (16.4 +/-1.1% vs. 7.7 +/- 2.1%; n = 3; p < 0.05) fraction after incubation in PI treated than in control plasma, respectively.


CONCLUSIONS
These findings suggest that modifications in lipoprotein surface charge alter CSA distribution within the LDL plasma fraction.
Wasan
Kishor M
KM
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall Avenue, Vancouver, British Columbia, Canada V6T 1Z3. kwasan@interchange.ubc.ca
Sivak
Olena
O
D000818:Animals; D016572:Cyclosporine / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D010316:Particle Size; D011817:Rabbits; D013499:Surface Properties
D008077:Lipoproteins, LDL; D016572:Cyclosporine