Improved Method for Determining Partition and Diffusion Coefficients in Human Dermis

Accurate values of partition and diffusion coefficients within the lower skin layers are among the information required to estimate skin concentrations of permeants following topical application. For highly lipophilic compounds these parameters also play a significant role in determining systemic absorption rates. In this study methodology is described for making more accurate in vitro measurements of partition and diffusion coefficients in dermis. Isolated human dermis obtained from surgical reduction was mounted in side-by-side diffusion cells in the presence and absence of a dialysis membrane (5000 MW cut-off) placed between the dermis and the donor solution. Permeation of N,N-diethyltoluamide (DEET) and diclofenac across the composite membrane system, as well as steady-state skin concentrations, were measured by radiochemical techniques. For the highly protein bound compound, diclofenac, dermis permeability, and partition coefficient determined in the presence of the dialysis membrane were significantly higher than those determined in its absence. No significant differences were observed for the moderately protein bound DEET. The results show that, in the absence of a stratum corneum barrier, attention must be given to the diffusion of soluble proteins in order to obtain accurate estimates of transport and partitioning parameters for highly protein bound solutes in dermis.