Flow microcalorimetry for human erythrocyte hemolysis induced by ionic drug binding

Abstract

The interactions of the ionic drugs chlorpromazine (CPZ), promethazine (PMZ), flufenamic acid (FA) and mefenamic acid (MA) with human erythrocyte membranes were compared by flow microcalorimetry, with respect to hemolytic activity and membrane uptake. Cationic drugs such as CPZ and PMZ bound to and/or penetrated the intramembranes, with small negative enthalpy and large positive entropy changes arising from hydrophobic interactions, and then induced hemolysis immediately as a result of drug binding, forming mixed micelles with the membrane lipids and disrupting the membrane structure. Anionic drugs such as FA and MA had two kinds of binding sites on the membrane surface; one strong binding site with large negative enthalpy and positive entropy changes, and some weak sites with a higher capacity and small negative entropy change, reflecting not only hydrophobic interaction but also ionic and van der Waals interactions. The first class of binding sites was already saturated when these drugs caused hemolysis.