Characterization of the Inclusion Mode of -Cyclodextrin Sulfate and Its Effect on the Chlorpromazine-Induced Hemolysis of Rabbit Erythrocytes

Abstract

The inclusion mode of -cycIodextrin sulfate (-CyD-sul) with a cationic drug, chlorpromazine, was investigated, and the effect of ß-CyD-sul on the hemolytic activity of chlorpromazine was compared with that of parent ß-CyD. The interaction of /f-CyD-sul with chlorpromazine was weaker than that of parent ß-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 P-CyD-sul with chlorpromazine. The inhibiting effect of parent ß-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 ß-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 ß-CyD-sul, and its inhibiting effect was greater than that of ß-CyD, because of the counterbalance of the opposite effects, i.e., internalization and externalization induced by chlorpromazine and ß-CyD-sul, respectively. © 1994, The Pharmaceutical Society of Japan. All rights reserved.