The effect of delivery system on the permeation and metabolism of alpha-tocopheryl acetate (alpha-TAc) was studied in micro-Yucatan pig skin, which closely resembles human skin. Various alpha-tocopheryl acetate formulations, including a simple isopropyl myristate (IPM) solution, an o/w emulsion, microemulsions, which differed in their oily phase content, and alcoholic and hydroalcoholic gels were made. A suitable HPLC method was developed and validated to separate and quantify alpha-TAc and alpha-tocopherol (alpha-T). Dulbecco's modified phosphate-buffered saline with 3% bovine serum albumin (DMPBS-BSA 3%) served as the receptor media to ensure tissue viability and to maintain skin conditions. Finite doses (5 microl) of the formulations were applied to viable pig skin using a statistically approved randomized complete block design. Data were analyzed using Tukey's studentized range test, and interday variability was estimated using an F-test. About 70% of the active was recovered from the wash, representing the amount adhering to the surface of the skin. alpha-TAc underwent metabolism in pig skin to the active antioxidant, alpha-T. The identity of the HPLC peaks were confirmed by spiking studies using known standards. The extent of metabolism was found to be formulation-dependent. No alpha-T was, however, detected in the stratum corneum. A higher extent of metabolism was obtained for the IPM solution, a microemulsion containing IPM as the oily phase, and the hydroalcoholic gel, when calculated based on the percent of total alpha-TAc permeated in the viable skin. Metabolism occurred in pig skin to the extent of 15-20% in terms of the total amount of alpha-TAc permeated in the viable skin and stratum corneum. Thus the topical delivery and metabolism of alpha-TAc were found to be dependent on formulation.