Electrorepulsion versus electroosmosis: Effect of pH on the iontophoretic flux of 5-fluorouracil

Purpose. To delineate the contributions of electrorepulsion and electroosmosis to the iontophoretic flux of 5-FU across porcine skin in vitro. Also, the isoelectric point (pI) of the skin model was determined. Methods. The electrotransport of 5-FU, anode-to-cathode ('anodal') and cathode-to-anode ('cathodal') was determined as a function of the pH of the electrolyte bathing the skin. Results. At pH 8.5, the drug (pK(a) ~8) is negatively charged and 'cathodal', viz. electrorepulsive, transport is much greater than that in the opposite direction. At pH 7.4, where ~25% of 5-FU is charged, electrorepulsive and electroosmotic ('anodal') fluxes are balanced. Decreasing the pH to 6, and then 5, reduces the percentage of ionized 5-FU such that 'anodal' electroosmosis dominates across the negatively-charged membrane. But, at pH 4, 'anodal' and 'cathodal' fluxes are again equal suggesting neutralization of the skin (i.e., pI ~ 4). This is confirmed at pH 3, where 'cathodal' electroosmosis dominates across the now net-positively charged barrier. Conclusions. Electrotransport is sensitive, mechanistically, to the properties of the permeant and of the skin; interactions of, for example, the drug or constituents of a formulation, that alter the barrier's net charge, can affect iontophoretic delivery. The pI of porcine ear skin is ~4.