Combined effect of d-limonene pretreatment and temperature on the rat skin permeation of lipophilic and hydrophilic drugs.

The combined effect of d-limonene and temperature on the skin permeation of lipophilic and hydrophilic penetrants has been investigated in rats in vitro. Prednisolone was used as a lipophilic penetrant, and glucose and isoniazid were used as hydrophilic ones, respectively. When the skin was pretreated with 30% ethanol without d-limonene, the steady state permeability coefficient (P) of every penetrant through the skin was difficult to calculate because of very low permeability. On the other hand, the cumulative amount of each penetrant increased with an increase in temperature when the skin was pretreated with 1.5% d-limonene in 30% ethanol. The Arrhenius plots of P values for glucose and isoniazid showed a linear relationship, and the activation energies of skin permeation were estimated to be 87.6 and 66.5 kJ/mol, respectively. When prednisolone was used as penetrant, however, the Arrhenius plot of P values exhibited a convex curvature. This may suggest that the combined use of d-limonene and temperature effectively changes the barrier structure of the non-polar pathway in the stratum corneum, while no synergistic effect was observed on the polar pathway.