Role of phospholipids in drug-LDL bindings as studied by high-performance frontal analysis/capillary electrophoresis.
The binding study between basic drugs ((S)-verapamil (VER) and (S)-propranolol (PRO)) and phospholipid liposomes was performed by using high-performance frontal analysis/capillary electrophoresis (HPFA/CE) in order to investigate the effect of oxidative modification of low-density lipoprotein (LDL) upon drug-binding affinity from molecule-based viewpoint. 1-Palmitoyl-2-oleoyl-phosphatidylcholine (POPC, 16:0, 18:1), 1-palmitoyl-2-linoleoyl-phosphatidylcholine (PLPC, 16:0, 18:2), dilauloyl-phosphatidylcholine (DLaPC, 12:0, 12:0), 1-palmitoyl-2-oleoyl-phosphatidyl-glycerol (POPG, 16:0, 18:1), and 1-palmitoyl-sn-glycero-3-phosphocholine (monoPPC, 16:0) were used to prepare the model liposomes. At physiological pH (pH 7.4), the model liposome prepared from POPG+POPC had negative net charges, while the total net charge of the other model liposomes (POPC liposome, PLPC liposome, DLaPC liposome, and monoPPC+POPC liposome) was zero. The drug and the model liposome mixed solutions were subjected to HPFA/CE, and the total binding affinities (nK) were calculated. The nK values of VER and PRO to POPG+POPC liposome were more than six and 10 times higher than those of other liposomes, respectively. On the other hand, the nK values of the model drugs to POPC liposome, PLPC liposome, DLaPC liposome and monoPPC+POPC liposome showed small differences less than twice. These results indicate that the electrostatic interaction plays an important effect on drug-liposome binding, and suggest that the increase in the negative charge of LDL phospholipids gives more significant effect on the drug-binding affinity of the basic drugs than the acyl-chain structure.
Kuroda
Yukihiro
Y
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Watanabe
Yoshinori
Y
Shibukawa
Akimasa
A
Nakagawa
Terumichi
T
D019075:Electrophoresis, Capillary / Q000379:methods; D008077:Lipoproteins, LDL / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D013678:Technology, Pharmaceutical / Q000379:methods*
D008077:Lipoproteins, LDL; D004364:Pharmaceutical Preparations; D010743:Phospholipids