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 hy drochloride (CPZ) or 15 mmol dm(-3) propantheline bromide (PB) by alpha-, b eta-, and gamma-cyclodextrins (CyDs) is measured as a function of CyD conce ntration and is correlated with the surface tension of its solution determi ned 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 gamma-CyD is larger than the 1:1 binding constant, whereas the converse result is observed for the PB-gamma -CyD system. This cooperative binding of CPZ to gamma-CyD would be ascribed to a higher tendency of CPZ to form dimer than that. of PB. Both the capab ilities of CyDs for hemolysis suppression and surface tension elevation are in the order beta-CyD > gamma-CyD > alpha-CyD for 0.7 mmol dm(-3) CPZ, whe reas those capabilities are in the order beta-CyD approximate to gamma-CyD > alpha-CyD for 15 mmol dm-3 PB. The bitter taste reduction and surface ten sion elevation for a 1.5 mmol dm-3 PB solution were both in the order beta- CyD > gamma-CyD > alpha-CyD. This discrepancy for PB is ascribed to the eff ects of self-association of PB and the 2:1 binding at the high PB concentra tion, The suppression of CPZ- or PB-induced hemolysis for beta- and gamma-C yDs can be quantitatively predicted from the observed surface tension data, regardless of the kind and concentration of CyD, but it is not the case fo r alpha-CyD, This exception is ascribed to weaker competitive binding of th ese drugs to alpha-CyD than that of membrane phospholipid.