Relationship between hemolytic concentrations and physicochemical properties of basic drugs, and major factors inducing hemolysis.

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Abstract
To clarify the differences in hemolytic activities between basic drugs and to identify the major factors inducing hemolysis, some tranquilizers and antihistaminics [promazine, promethazine, trimeprazine, perazine, chlorpromazine, prochlorperazine, levomepromazine, prothipendyl, homochlorcyclizine and carpipramine] were compared with each other as regards hemolytic activities [using human erythrocytes], van der Waals volume (V), pKa, partition coefficient (octanol/water, P), lipid spin labeling and membrane/buffer partition ratio (Pm/b), and correlation analyses were carried out among these parameters. The best correlation was between logarithmic Pm/b for drugs and 1/C1 (C1; the initial concentration inducing hemolysis, r = 0.877, P < 0.01) or 1/C50 (C50; the concentration inducing 50% hemolysis, r = 0.924, P < 0.01). Correlations though not as good) were observed between the logarithmic V (r = 0.708, P < 0.05; r = 0.780, P < 0.05) or the fluidity of lipids (r = 0.711, P < 0.05; r = 0.619) and 1/C1 or 1/C50, respectively. No correlation was found between P and hemolytic concentrations. The amount of drugs penetrated into the membrane is probably a major factor in the induction of hemolysis, and a large molecular volume of a drug, increased fluidity of the membrane lipids and un-ionized concentration of the drug significantly affect the drug-induced hemolytic process.