PHARMACOKINETICS OF 2-ETHYL-1,3-HEXANEDIOL .3. IN-VITRO SKIN PENETRATION COMPARISONS USING THE EXCISED SKIN OF HUMANS, RATS, AND RABBITS

Excised skin from Fischer 344 rats, New Zealand White rabbits, and hum an females (obtained from mammoplasty patients) were compared for thei r in vitro skin penetration potential with 2-[C-14]ethyl-1,3-hexanedio l (EHD). EHD was applied as both an undiluted dose and a 3% v/v aqueou s dose using a flowthrough skin penetration chamber design and was ana lyzed over 0-6 hr. The undiluted dose was equivalent to a 150 mg/kg do se used in vivo with rats (Frantz et at, Drug Metab. Dispos. 20(1), 6- 18, 1999), but normalized on a per cm(2) surface area basis, and appli ed under occluded conditions (covered as for in vivo studies). Undilut ed applications of EHD did not substantially penetrate skin, with effl uent recoveries of approximately 0.9% of the applied dose for human sk in, 2-4% for rat skin, and 3-6% for rabbit skin. By comparison, nonocc luded human skin showed lower effluent radioactivity (0.6%), which was attributed to EHD evaporation from skin. With undiluted EHD, approxim ately 97% of the recovered C-14 was an unabsorbed dose for human skin, with 94% for rat skin and 85% for rabbit skin (expressed as a percent age of the recovered dose). Based on HPLC analysis of effluent samples , 99-100% of the undiluted [C-14]EHD penetrated rat, rabbit, and human skin in the unmetabolized form. In contrast, approximately 5% of the applied aqueous dose was recovered in the effluents for human skin, wh ile 6-9% appeared in effluents for rat skin; rabbit skin was not evalu ated for aqueous doses. The fraction of unabsorbed aqueous EHD dose to taled 53% of the applied dose for human skin and 63% for rat skin. Eva porative loss of undiluted [C-14]EHD was also measured (captured on ac tivated charcoal) in separate experiments and compared with a known st andard chemical, N,N[C-14]diethyl-m-toluamide (DEET). Evaporation of E HD was clearly a competing factor with penetration, particularly for h uman skin preparations, and evaporative losses were similar to those s een in previous studies. Penetration of skin was also greater for both EHD and DEET when evaporation was not permitted (stoppered chamber). Permeability constant (k(p)) values were calculated using the pseudo s teady-state slopes from plots for cumulative mg/cm(2) penetration vs t ime. For undiluted EHD, human skin had the slowest penetration rate, w hile rabbit skin k(p) values were the largest. The k(p) values for wat er solutions of EHD on rat and human skin demonstrated a slightly high er penetration, with values of the same order of magnitude as that obs erved for a concurrently run [C-14]ethanol control. The minimal skin p enetration observed in vitro in this study, taken together with in viv o percutaneous pharmacokinetic studies (Frantz et at, 1992) and the kn own percutaneous toxicology of EHD, suggests that penetration through human skin and systemic adverse effects should be minimal. (C) 1995 So ciety of Toxicology