In vitro penetration of the dopamine D2 agonist N-0923 with and without Azone

The penetration of the dopaminergic D2 agonist S(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923) was evaluated in vitro on full-thickness rat skin, using the Franz diffusion cell. The drug was tested as the N-0923 . HCl salt as well as the N-0923 base. The penetration-enhancing effect of Azone was studied in a vehicle concentration of 5%, or after pretreating shaven rat skin in vivo, at several time intervals before the in vitro experiment, with a solution containing 1 or 5% Azone. From the vehicle containing 60% ethanol, 20% propylene glycol and 20% water, the extent of penetration through rat skin was relatively low for the base and even lower for the salt. The introduction of Azone into the vehicle in a final concentration of 5% resulted in a 6-fold decrease in penetration for the free base. Nevertheless, penetration of the salt increased about 12-fold in extent during the first 12 h, after which it declined to almost zero. The lag time was reduced from 13 to 5 h. Pretreatment of rat skin in vivo with an ethanol-propylene glycol-water solution containing 5% Azone resulted in a 12-fold increase in flux for the salt, a 2-fold increase in flux for the base and a decrease in lag time to about the same values for both N-0923 . HCl and N-0923 base. In vivo pretreatment of rat skin with a solution containing 1% Azone had no significant effect on the flux and lag time vs controls. This study indicates that Azone may have potential in facilitating the transdermal application of N-0923, principally through pretreatment of the skin to enhance absorption. This may allow it to circumvent its considerable oral first-pass metabolism.