OBJECTIVE N-Alkylamides are a large group of bioactive molecules found in several plants from the genera Echinacea, Xanthoxylum and Spilanthes. Extracts and formulations derived from these plants are not only orally used, but also applied on the skin as well. However, there is currently no specific information available about the intrinsic local pharmacokinetics of N-alkylamides after topical application on human skin, questioning the role of this mode of administration. The present study investigates the transdermal behaviour of spilanthol, a prominent N-alkylamide. METHODS Two pharmaceutically accepted dose solutions (ethanol and propylene glycol based aqueous donor vehicles), combined with three different receptor fluids (PBS, PBS+0.5% HPbetaCD, EtOH/H(2)O (30:70, v/v)), were applied on split-thickness human skin in a Franz diffusion cell (FDC) system. Fundamental permeation characteristics of spilanthol in a solvent-independent way (100% aqueous dose solution) were also obtained using an extrapolation approach with different organic solvent/H(2)O ratios. CONCLUSIONS We demonstrated for the first time that spilanthol permeates the skin. The following aqueous-extrapolated primary transdermal parameters were obtained (mean+/-SEM): K(p,aq)=3.31 (+/-0.29)x10(-3)cm/h, D(m,aq)=1.86 (+/-0.09)x10(-4)cm(2)/h and K(m,aq)=7.28 (+/-1.59)x10(-1). Partitioning (K(m)) was strongly dependent on the donor solution composition, while diffusion (D(m)) was mainly influenced by the receptor fluid composition.