Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships

Permeability coefficients for 114 compounds across excised human skin in vitro were taken from Kirchner et al. Forty-seven descriptors were calculated encompassing the relevant physicochemical parameters of the compounds. Quantitative structure-permeability relationships (QSPRs) were developed using least-squares regression analysis. A two-parameter QSPR, describing the permeability coefficients (K-p) across excised skin, was obtained: log K-p = 0.772 log P -0.0103 M-r - 2.33 where log P is the logarithm of the octanol-water partition coefficient and ill, is molecular mass. This equation indicates that percutaneous absorption is mediated by the hydrophobicity and the molecular size of the penetrant. Comparison with a QSPR based on penetration across a synthetic (polydimethylsiloxane) membrane suggests that the mechanisms of drug flux across polydimethylsiloxane membranes and excised human skin are significantly different. (C) 1999 Elsevier Science B.V. All rights reserved.