Partitioning, diffusivity and clearance of skin permeants in mammalian dermis

The partition coefficients (K-de) and diffusivities (D-de) of compounds in mammalian dermis were examined through an analysis of in vitro permeation data obtained from the literature combined with experimental results with the test permeant, H-3-testosterone. The literature data involved 26 compounds ranging in molecular weight from 18 to 476 Da and four species-human, guinea pig, rat and mouse. Testosterone was studied by permeation and desorption measurements employing excised human dermis in the presence and absence of external serum albumin. Mathematical models for both K-de and D-de were developed. The K-de model involved ionization, binding to extravascular serum proteins and partitioning into a small lipid compartment. The D-de model employed a free diffusivity with a liquid-like size dependence multiplied by a binding factor derived from K-de,. An additional analysis considered in vivo dermal concentration profiles of topically applied permeants. Literature data for 5 of 6 permeants were shown to be well described by a previously published model for capillary clearance in the dermis, which leads to an exponential decay of concentration with depth. Computed decay lengths (I le values) ranged from 2 10 to 920 mu m, and the corresponding clearance rate constants k(de) ranged from 0.9 x 10(-4) to 14 x 10(-4)s(-1) (n = 8). Departures from the exponential decay profile are discussed in terms of non-uniform capillary clearance and incomplete attainment of a steady-state. (C) 2007 Elsevier B.V. All rights reserved.