Shiotani K, Uehata K, Irie T, Hirayama F, Uekama K
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Chem Pharm Bull (Tokyo). 1994 Nov;42(11):2332-7. doi: 10.1248/cpb.42.2332.
The inclusion mode of beta-cyclodextrin sulfate (beta-CyD-sul) with a cationic drug, chlorpromazine, was investigated, and the effect of beta-CyD-sul on the hemolytic activity of chlorpromazine was compared with that of parent beta-CyD. The interaction of beta-CyD-sul with chlorpromazine was weaker than that of parent beta-CyD, probably because of the steric or electrostatic repulsion between anionic sulfate groups and hydrophobic phenothiazine moiety. Spectroscopic studies, including pH- and salt-effects, as well as thermodynamic parameters, suggested that both electrostatic and hydrophobic interactions are operative in the inclusion complexation of beta-CyD-sul with chlorpromazine. The inhibiting effect of parent beta-CyD on the chlorpromazine-induced hemolysis of rabbit erythrocytes was accounted for by the decreased fraction of free drug through the complexation. In the case of beta-CyD-sul, the hemolysis and binding of the drug to the erythrocyte membrane was higher than those estimated from the fraction of free drug, probably due to the increased hydrophobicity of the drug through the complexation. However, the chlorpromazine-induced shape change of the erythrocytes was significantly suppressed by beta-CyD-sul, and its inhibiting effect was greater than that of beta-CyD, because of the counterbalance of the opposite effects, i.e., internalization and externalization induced by chlorpromazine and beta-CyD-sul, respectively.
研究了硫酸β-环糊精（β-CyD-sul）与阳离子药物氯丙嗪的包合模式，并将β-CyD-sul对氯丙嗪溶血活性的影响与母体β-环糊精进行了比较。β-CyD-sul与氯丙嗪的相互作用比母体β-环糊精弱，这可能是由于阴离子硫酸基团与疏水性吩噻嗪部分之间的空间或静电排斥作用。包括pH和盐效应以及热力学参数在内的光谱研究表明，静电和疏水相互作用在β-CyD-sul与氯丙嗪的包合络合中均起作用。母体β-环糊精对氯丙嗪诱导的兔红细胞溶血的抑制作用是由于通过络合作用使游离药物的比例降低。在β-CyD-sul的情况下，药物与红细胞膜的溶血和结合高于根据游离药物比例估算的值，这可能是由于通过络合作用药物的疏水性增加。然而，β-CyD-sul显著抑制了氯丙嗪诱导的红细胞形状变化，并且其抑制作用大于β-CyD，这是因为分别由氯丙嗪和β-CyD-sul诱导的内化和外化这两种相反作用相互抵消。
