Structure-permeability relationships for transcorneal penetration

The main objective of this study was to determine, by using a literature da ta set of 112 corneal permeability measurements, whether a statistically si gnificant structure-permeability relationship (SPR) for predicting the tran sport of structurally diverse chemicals across the rabbit cornea could be d eveloped on the basis of just two physicochemical properties, the logarithm of the octanol-water partition coefficient (logP), and molecular weight (M W), which provide measures of lipophilicity and molecular size, respectivel y. A secondary objective was to identify additional physicochemical propert ies that are predictive of corneal permeability, and to use these as descri ptors in an SPR. To achieve the first objective, multiple linear regression of corneal permeability against logP and MW was performed, and was found t o produce a statistically significant (p < 0.001) SPR with stable coefficie nts. The second objective was achieved by carrying out stepwise regression analysis of corneal permeability against a number of calculated physicochem ical properties; this identified three variables, representing lipophilicit y (logP), molecular shape (the third-order kappa index [kappa 3]), and hydr ogen-bonding capacity (n(H)) A three-variable SPR based on these descriptor s was also statistically significant (p < 0.001) and had stable coefficient s. Mechanistically based SPRs, such as the ones reported in this paper, cou ld be used during the drug discovery process as a first step in the predict ion of transcorneal delivery.