Rabbit ears were single-pass perfused with a buffer solution containing either 6% hetastarch or 5% bovine serum albumin. Hydrocortisone 21-butyrate (5 mM), diflunisal (17 mM) or permethrin (33 mM) was added to isopropyl myristate with 5% polyethylene, and applied to about 40% of the epithelial surface area of the ear. Hydrocortisone 21-butyrate or permethrin were not found in the effluent with hetastarch or albumin. Following cutaneous ester hydrolysis, the appearance rate of hydrocortisone was about 4 pmol/min per cm2 2,000 or when the xenobiotic is ionized at physiological pH. In general, for all substances investigated with our perfusion model thus far, the appearance rates decreased with rising distribution coefficient (n-octanol/buffer pH 7.4). High lipophilicity hinders the release from isopropyl myristate and the penetration through the skin.