The molecular basis of the potent transdermal enhancement activity of a series of iminosulfuranes, structure provided where X = H, Cl, Br, and I, is being investigated skin models. It has been shown (J. Lipid Res. 46(2005), 2192-2201.) that correlations exist between the activity of the aforementioned transdermal penetration enhancers (TPE) and the extent to which these agents bind to DMPC vesicles and perturb the gel to liquid crystal phase transition measured by calorimetry. The degree to which the perturbation of these compounds extends into the bilayer interior in contrast to surface activity is unclear. To gain insight into this issue, the 31P NMR resonance from DMPC and DMPC-cholesterol unilamellar vesicles have been split by the slowly penetrating paramagnetic metal ion Pr+3. The extent to which this perturbation is attenuated by transdermal penetration enhancers has been investigated as a function of Pr+3 exposure time and iminosulfurane concentration. The effect of these iminosulfuranes on bilayer integrity is also being explored by monitoring the induced release of carboxyfluorescein from DMPC and DMPC- cholesterol unilamellar vesicles.