Quantitative Prediction of the Suppression of Drug-Induced Hemolysis by Cyclodextrins from Surface Tension Data

The suppression of hemolysis induced with 0.7 mmol dm - 3 chlorpromazine hydrochloride (CPZ) or 15 mmol dm - 3 propantheline bromide (PB) by α-, β-, and γ-cyclodextrins (CyDs) is measured as a function of CyD concentration and is correlated with the surface tension of its solution determined at 310 K. The surface tension data allow us to estimate the 1:1 and 2:1 binding constants of CPZ with CyDs as well as the dimerization constant of CPZ. The 2:1 binding constant of CPZ with γ-CyD is larger than the 1:1 binding constant, whereas the converse result is observed for the PB−γ-CyD system. This cooperative binding of CPZ to γ-CyD would be ascribed to a higher tendency of CPZ to form dimer than that of PB. Both the capabilities of CyDs for hemolysis suppression and surface tension elevation are in the order β-CyD > γ-CyD > α-CyD for 0.7 mmol dm - 3 CPZ, whereas those capabilities are in the order β-CyD ≈ γ-CyD > α-CyD for 15 mmol dm - 3 PB. The bitter taste reduction and surface tension elevation for a 1.5 mmol dm - 3 PB solution were both in the order β-CyD > γ-CyD > α-CyD. This discrepancy for PB is ascribed to the effects of self-association of PB and the 2:1 binding at the high PB concentration. The suppression of CPZ- or PB-induced hemolysis for β- and γ-CyDs can be quantitatively predicted from the observed surface tension data, regardless of the kind and concentration of CyD, but it is not the case for α-CyD. This exception is ascribed to weaker competitive binding of these drugs to α-CyD than that of membrane phospholipid.