Epidermal permeability-penetrant structure relationships: 4, QSAR of permeant diffusion across human stratum corneum in terms of molecular weight, H-bonding and electronic charge

Principal components analysis (PCA) and multivariate regression analysis (M RA) are used to assess the predictors of permeant diffusion across human st ratum corneum. Log(D/h), was estimated from log k(p) + 0.024 - 0.59 log K-o ct,, where D = diffusion coefficient (cm(2)/h), h = path length (cm), k(p) permeability coefficient (cm/h), K-oct = partition coefficient (octanol/wat er). Molecular weight (MW) with (1) scaled H-bonding parameters alpha and b eta, or (2) summed modulus of partial charge from molecular modelling were tested as predictors of (D/h). Charge may be computed for any molecule, whi lst alpha and beta values are generally unavailable for molecules of biolog ical interest. PCA suggests a dominant permeation pathway since 93% of data variation is in PC1 of log (D/h), MW and charge and 82% in PC1 of log (D/h ), MW, alpha and beta. MRA using MW, alpha and beta is unsatisfactory becau se of collinearity amongst predictors. The best predictor was the product M W*charge. Similarity of the eigenvectors in PCA and normalised coefficients in MRA indicates that charge and MW are equally important predictors of di ffusion. (C) 2000 Elsevier Science B.V. All rights reserved.