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Alternatives to Laboratory Animals - ATLA

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Structure–permeability Relationships for Transcorneal Penetration

Andrew P. Worth and Mark T.D. Cronin

The main objective of this study was to determine, by using a literature data set of 112 corneal permeability measurements, whether a statistically significant structure–permeability relationship (SPR) for predicting the transport of structurally diverse chemicals across the rabbit cornea could be developed on the basis of just two physicochemical properties, the logarithm of the octanol–water partition coefficient (logP), and molecular weight (MW), which provide measures of lipophilicity and molecular size, respectively. A secondary objective was to identify additional physicochemical properties that are predictive of corneal permeability, and to use these as descriptors in an SPR. To achieve the first objective, multiple linear regression of corneal permeability against logP and MW was performed, and was found to produce a statistically significant (p < 0.001) SPR with stable coefficients. The second objective was achieved by carrying out stepwise regression analysis of corneal permeability against a number of calculated physicochemical properties; this identified three variables, representing lipophilicity (logP), molecular shape (the third-order kappa index [Κ3]), and hydrogen-bonding capacity (nH). A three-variable SPR based on these descriptors was also statistically significant (p < 0.001) and had stable coefficients. Mechanistically based SPRs, such as the ones reported in this paper, could be used during the drug discovery process as a first step in the prediction of transcorneal delivery.