CUTANEOUS METABOLISM OF NITROGLYCERIN INVITRO .2. EFFECTS OF SKIN CONDITION AND PENETRATION ENHANCEMENT

The effects of skin storage. skin preparation, skin pretreatment with a penetration enhancer, and skin barrier removal by adhesive tape-stri pping on the concurrent cutaneous transport and metabolism of nitrogly cerin (GTN) have been studied in vitro using hairless mouse skin. Stor ing the skin for 10 days at 4-degrees-C did not alter barrier function to total nitrate flux [GTN + 1.2-glyceryl dinitrate (1,2-GDN) + 1,3-g lyceryl dinitrate (1,3-GDN)]. However, metabolic function was signific antly impaired and suggested at least fivefold loss of enzyme activity . Heating skin to 100-degrees-C for 5 min appreciably damaged hairless mouse skin barrier function. The ability to hydrolyze GTN was still p resent, however, and remained constant over the 10-hr experimental per iod, in contrast to the "control," which showed progressively decreasi ng enzymatic function with time. Pretreatment of hairless mouse skin i n vivo (prior to animal sacrifice, tissue excision, and in vitro trans port/metabolism studies) with 1-dodecylazacycloheptan-2-one (Azone), a putative penetration enhancer, significantly lowered the skin barrier to nitrate flux (relative to the appropriate control). Again, barrier perturbation resulted in essentially constant metabolic activity over the observation period. The ratio of metabolites formed (1,2-GDN/1,3- GDN) was increased from less than unity to slightly above 1 by the Azo ne treatment. Adhesive tape-stripping gradually destroyed skin barrier function by removal of the stratum corneum. The effects of 15 tape-st rips were identical to those of Azone pretreatment: a greatly enhanced flux, a constant percentage formation of metabolites over 10 hr (once again), and an increase in the 1,2-GDN/1,3 GDN ratio. Overall, the ex periments caution that, for transdermal drug delivery candidates susce ptible to skin metabolism, the status of barrier function (enhancer pr etreated, skin damage or disease, etc.) may significantly affect syste mic availability.