Mechanisms and surface chemical prediction of imipramine-induced hemolysissuppressed by modified cyclodextrins

The suppression of imipramine hydrochloride (IMP)- induced hemolysis by nat ive cyclodextrins (alpha-, beta-, and gamma -CDs) and beta -CD derivatives is measured as a function of CD concentration and is quantitatively correla ted with the surface tension of the solution determined at 37.0 degreesC. T he modified beta -CDs are more or less adsorbed onto the air-water interfac e and occupy larger areas than the wider rim of P-CD. The surface tension d ata at low CD concentrations in the presence of 3 mM IMP allow us to estima te the 1:1 binding constants of IMP with CDs. Both the capabilities of hemo lysis suppression and surface tension elevation for 3 mM IMP are strong in the order carboxymethyl-beta -CD (CM) > beta -CD approximate to 6-O-glucosy l-beta -CD (G(1)) > gamma -CD > 2-hydroxypropyl-beta -CD (HP) > alpha -CD g reater than or equal to 2,6-di-O-methyl-beta -CD (DM). The suppression of I MP-induced hemolysis is ascribed to the decrease in the concentration of fr ee IMP molecules. This concentration can be quantitatively estimated from t he surface tension data determined at 37 degreesC. Therefore, the suppressi on of IMP-induced hemolysis by most of the CDs can be quantitatively predic ted from these surface tension data, regardless of the kind and concentrati on of CD. However, alpha -CD, HP, and DM are outliers of this prediction. T his failure for alpha -CD and HP is ascribed to their weaker competitive bi nding to IMP than to membrane phospholipid. Because DM has a strong hemolyt ic activity, it does not almost suppress the IMP-induced hemolysis. (C) 200 1 Wiley-Liss, Inc. and the American Pharmaceutical Association.