N. Funasaki et al., Mechanisms and surface chemical prediction of imipramine-induced hemolysissuppressed by modified cyclodextrins, J PHARM SCI, 90(8), 2001, pp. 1056-1065
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.