KINETICS OF QUININE DEUTEROHEMIN BINDING

The interaction of quinine with free hemin is of importance for the an timalarial effect of the drug in infected erythrocytes. We have invest igated the kinetics of the complex formation of quinine with deuterohe min using the temperature jump relaxation method. We use ethyleneglyco l-water mixtures as a solvent, where sufficient solubility for both sp ecies is provided and dimerization of the hemins, which involves mu-ox o bridges, can be controlled. Equilibrium and kinetic data for the dim erization of deuterohemin are given at 30 and 50 vol% ethyleneglycol. Binding of quinine is significantly slower than dimerization. Both pro cesses are well separated on the time axis and yield a relaxation prog ress curve which is described with high accuracy by two exponential te rms. The slow relaxation process is analyzed with respect to a 1 : 1 c omplex formation. This is the simplest mechanism which accounts for th e present data, leading at 30 vol% ethyleneglycol, pH 7.5 to a binding constant of 10(4) M-1 and rate constants of 4.4 x 10(5) M-1 s-1 for t he association and 44 s-1 for the dissociation step. However, there is evidence from the fast relaxation process that monomeric and dimeric hemin exhibit different reactivity. There is a strong decrease in rate with increasing pH. The implication of the results with respect to th e proposed mechanisms of complex formation with quinoline drugs is dis cussed.