To determine the electromigration and electroosmotic contributions to the iontophoretic delivery of lidocaine hydrochloride, in addition to the more-lipophilic quinine and propranolol hydrochlorides, in the presence and absence of background electrolyte.In vitro experiments, using excised pig ear skin and both vertical and side-by-side diffusion cells, were performed as a function of drug concentration and with and without background electrolytes in the anodal formulation. Concomitantly, the contribution of electroosmosis in each experimental configuration was monitored by following the transport of the neutral, polar marker molecule, mannitol.Electromigration was the dominant mechanism of drug iontophoresis (typically representing approximately 90% of the total flux). In the presence of background electrolyte, lidocaine delivery increased linearly with concentration as it competed more and more effectively with Na+ to carry the charge across the skin. However, iontophoretic delivery of quinine and propranolol increased non-linearly with concentration. Without electrolytes, on the other hand, electrotransport of the three drugs was essentially independent of concentration over the range 1-100 mM. Transport efficiency of lidocaine was approximately 10%, whereas that of the more lipophilic compounds was significanly less, with the major charge carrier being Cl- moving from beneath the skin into the anodal chamber. Both quinine and propranolol induced a concentration-dependent attenuation of electroosmotic flow in the normal anode-to-cathode direction.Dissecting apart the mechanistic contributions to iontophoretic drug delivery is key to the optimization of the formulation, and to the efficient use of the drug substance.