Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action

The effect of various oxygen-containing monoterpenes such as cineole, menthol, a-terpineol, menthone, pulegone and carvone was investigated on ex vivo permeation of zidovudine (AZT) across rat skin. Furthermore, saturation solubility of AZT, its stratum corneum (SC)/vehicle partition coefficient and activation energy for diffusion across skin with or without terpene(s) in vehicle (66.6% ethanol in water) were determined to understand their mechanism of action. All the terpenes studied significantly increased transdermal flux of AZT in comparison to vehicle (p < 0.05) and their enhancement activities are in the following decreasing order: cineole>menthol>menthone approximate to pulegone approximate to alpha-terpineol>carvone>vehiclewater. On the other hand, saturation solubility and SC/vehicle partition coefficient of AZT were not significantly altered (p>0.05) by terpenes. Activation energies of AZT permeation across rat skin from water, vehicle and cineole in vehicle were measured to be 20.4, 18.6 and 10.6 kcal/mol, respectively. Interactions between terpenes and SC lipids were studied with molecular modeling and found that terpenes form hydrogen bonds (bond lengths < 2 Angstrom) with lipid head groups. The mechanism of permeation enhancement of AZT by terpenes was explained with thermodynamic activity, SC/vehicle partition coefficient, activation energy and molecular modeling studies. (C) 2004 Elsevier B.V. All rights reserved.