Scientific Publications by FDA Staff

Pharm Res 2017 Jan;34(1):217-28

The tritiated water skin barrier integrity test: considerations for acceptance criteria with and without 14C-octanol.

Lehman PA, Beatch K, Raney SG, Franz TJ

PURPOSE: A study was designed to assess barrier integrity simultaneously using separate compounds (probes) for polar and non-polar pathways through the skin, 3H2O and 14C-octanol, respectively; and to determine whether the two probe approach could better define barrier integrity. METHODS: A 5-min dose of water containing 3H2O and 14C -octanol was applied to ex vivo human skin mounted in Franz diffusion cells. The receptor solution was sampled at 30 min, analyzed for 3H and 14C content, and the correlation between water and octanol absorption was determined by statistical tests suitable for non-normally distributed data. This study was conducted on skin from 37 donors with from 3 to 30 replicate skin sections per donor (a total of 426 sections). RESULTS: The correlation between 3H2O and 14C-octanol absorption was low (Pearson correlation coefficient = 0.3485). The 3H2O absorption cutoff used in this study to select for a normal skin barrier rejected some sections in which 14C-octanol absorption was within normal limits and accepted others in which 14C-octanol absorption was abnormally high. The converse was true for 3H2O absorption when the 14C-octanol-based cutoff was used. CONCLUSIONS: The results of the 3H2O test or of similar tests that primarily assess the permeability of polar pathways through the skin may not necessarily provide information relevant to the absorption of highly lipophilic compounds. Octanol, or another molecule that more closely matches the physicochemical attributes of the test compound, may characterize properties of the skin barrier that are more relevant to compounds of low water solubility.