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ToxSci Advance Access originally published online on September 14, 2005
Toxicological Sciences 2005 88(2):434-446; doi:10.1093/toxsci/kfi319
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A Study of the Relationship between Cornea Permeability and Eye Irritation Using Membrane-Interaction QSAR Analysis

Yi Li, Jianzhong Liu, Dahua Pan and A. J. Hopfinger1

Laboratory of Molecular Modeling and Design (MC 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231

Received July 7, 2005; accepted September 6, 2005

A methodology termed membrane-interaction QSAR (MI-QSAR) analysis has been used to develop QSAR models to predict drug permeability coefficients across cornea and its component layers (epithelium, stroma, and endothelium). From a training set of 25 structurally diverse drugs, significant QSAR models are constructed and compared for the permeability of the cornea, epithelium, and stroma plus endothelium. Cornea permeability is found to depend on the measured distribution coefficient of the drug, the cohesive energy of the drug, the total potential energy of the drug-membrane "complex," and three other energy refinement descriptor terms. The endothelium may be a more important barrier in cornea permeation than the stroma. Moreover, an investigation of the correlation between cornea permeation and eye irritation is presented as an example of a cross study on different ADMET properties using MI-QSAR analysis. Thirteen structurally diverse drugs, whose molar-adjusted eye irritation scores (MES) have been measured using the Draize rabbit-eye test, were chosen as an eye irritation comparison set. A poor correlation (R2 = 0.0232) between the MES measures and the predicted cornea permeability coefficients for the drugs in the eye irritation set suggests there is no significant relationship between eye irritation potency and the cornea permeability.

Key Words: cornea permeability; eye irritation; membrane-interaction quantitative structure-activity relationships (MI-QSAR).


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