The binding of a drug such as Quinine with neutral and negatively charged small unilamellar lipid vesicles at pH 7 and 37 degrees C was investigated. Changes in the fluorescence properties of the drug after association with the liposomes were used to obtain binding isotherms over a range of phospholipid compositions at different ionic strengths. Under such conditions, the association was strongly enhanced by the negative net charge of the bilayer but diminished by the increasing presence of electrolytes in the aqueous media. Binding data were analyzed in terms of a surface partition equilibrium without and after correcting for electrostatic effects by means of the Gouy-Chapman theory. The intrinsic (hydrophobic) constant, obtained after charge correction, was smaller than the apparent binding constant determined without taking into account such an effect. A new analysis considering the two components not fully dissociated and affected by an identical screening factor has been introduced. It yielded rather similar hydrophobic partition coefficients for all conditions, independent of both the surface charge density of the lipid vesicles and the ionic strength, with an average value estimated to be (3 +/- 1) x 10(3) M(-1). All the findings suggested that the association of Quinine to liposomes is controlled primarily through electrostatic attractions, and, in a lesser extent, by hydrophobic forces. Because electrostatic and hydrophobic interactions play a crucial role in both the drug-membrane affinity and the location of the drug, their quantitative evaluation can shed light on the mechanism for a next therapeutic "action."