The contributions of several proposed mechanisms by which fatty acids and amines might increase skin permeation rates were assessed. Permeation rates of model diffusants with diverse physicochemical properties (naloxone, testosterone, benzoic acid, indomethacin, fluorouracil, and methotrexate) through human skin were measured in vitro. The enhancers evaluated were capric acid, lauric acid, neodecanoic acid, and dodecylamine. Increased drug solubility in the vehicle, propylene glycol (PG), in some cases accounted for the increases in flux in the presence of adjuvants, since permeability coefficients were unchanged. Partition coefficients of some drugs into isopropyl myristate or toluene were increased by the adjuvants, but this did not occur for combinations of an acid with a base (adjuvant-drug or drug-adjuvant). Increases in flux not accounted for by increases in drug solubility or partitioning were assumed to involve disruption of the barrier function of skin (increased skin diffusivity). All fatty acids increased skin diffusivity of naloxone, testosterone, indomethacin, and fluorouracil but not of methotrexate or benzoic acid. Dodecylamine increased skin diffusivity only for fluorouracil. Capric acid and dodecylamine, but not lauric acid or neodecanoic acid, increased the skin permeation rate of PG, suggesting that enhanced solvent penetration could also be involved as a mechanism for increased skin permeation of the drug. However, the increase in PG flux due to dodecylamine was nullified when methotrexate was added to the vehicle, possibly because of a dodecylamine/methotrexate interaction. These studies demonstrate that drug solubilization in the vehicle, increased partitioning, increased solvent penetration, and barrier disruption each can contribute to increased skin permeation rates in the presence of fatty acids and amines.(ABSTRACT TRUNCATED AT 250 WORDS)