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 (MRA) are used to assess the predictors of permeant diffusion across human stratum corneum. Log(D/h), was estimated from logk(p)+0.024-0.59 logK(oct), where D=diffusion coefficient (cm(2)/h), h=path length (cm), k(p) permeability coefficient (cm/h), K(oct)=partition coefficient (octanol/water). Molecular weight (MW) with (1) scaled H-bonding parameters alpha and beta, or (2) summed modulus of partial charge from molecular modelling were tested as predictors of (D/h). Charge may be computed for any molecule, whilst alpha and beta values are generally unavailable for molecules of biological 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 because of collinearity amongst predictors. The best predictor was the product MW*charge. Similarity of the eigenvectors in PCA and normalised coefficients in MRA indicates that charge and MW are equally important predictors of diffusion.
Pugh
W J
WJ
The Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, UK. pugh@cardiff.ac.uk
Degim
I T
IT
Hadgraft
J
J
D003627:Data Interpretation, Statistical; D004058:Diffusion; D006860:Hydrogen Bonding; D008970:Molecular Weight; D012044:Regression Analysis; D012867:Skin / Q000737:chemistry*; D012869:Skin Absorption; D013329:Structure-Activity Relationship