The objective of this study was to investigate the drug adsorption process in human skin using in vitro streaming potential measurements. Streaming potential is an electrokinetic phenomenon, which reflects both the charge density and the pore size of a membrane. Thus, the adsorption of charged solutes on the pore walls can be detected as a change of streaming potential, viz., as a change in the slope deltaE/deltaP. In these streaming potential measurements, hydrophilic nadolol and luteinizing hormone-releasing hormone, and lipophilic propranolol and Nafarelin were used as model drugs. As could be expected, the hydrophilic drugs did not change the slope. The more lipophilic propranolol and Nafarelin, instead, changed the slope. Propranolol changed the slope gradually from negative to positive when the concentration was increased from 1 to 10 mM. With Nafarelin, a straight line with a slope of about 0 was obtained at pH 7.3 and an ascending curve at pH 4.2. These results indicate that the negative charges on the pore walls of human skin are blocked by adsorption of the lipophilic cations. The adsorption of lipophilic cations in the skin alters the permselectivity of the skin, which, in turn, may lead to the inhibition of electroosmotic flow across the skin during iontophoresis and to the shut down of transdermal drug permeation of higher molecular weight drugs.