A PREDICTIVE ALGORITHM FOR SKIN PERMEABILITY - THE EFFECTS OF MOLECULAR-SIZE AND HYDROGEN-BOND ACTIVITY

Purpose. To develop a predictive algorithm of nonelectrolyte transport through skin based upon a partitioning-diffusion model. Methods. Drug permeability is described by a partitioning-diffusion equation. Throu gh free-energy relationships, partitioning is related to the drug's mo lecular volume (MV), and hydrogen bond donor (H-d) and acceptor (H-a) activity. Diffusion is related to the drug's MV using a theory of diff usion through lipid lamellae based on free-volume fluctuations within the lipid domain. These two explicit descriptions are combined to give an equation describing permeability in terms of the permeant's physic al properties. The aqueous permeability coefficients of 37 nonelectrol ytes through human epidermis were evaluated as a function of these phy sical properties using a multiple regression analysis. Result. The res ults of the regression analysis show that 94% of the variability in th e data can be explained by a model which includes only the permeant's MV, H-d and H-a. These results further provide an algorithm to predict skin permeability based upon the values of these parameters. In addit ion, the relative contribution of various chemical functional groups ( e.g., -COOH) is derived, and can be used to predict skin transport fro m drug structure alone. Conclusions. A biophysically relevant model of drug transport through human skin is derived based solely on the phys ical properties of the drug. The model provides an algorithm to predic t permeability from the drug's structure andior physical properties. M oreover, the model is applicable to a number of lipid barrier membrane s, suggesting a common transport mechanism in all.