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

Abstract

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 M r 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.