| Drug delivery to the eye presents significant challenges as topically- and systemically-applied drugs hardly reach target tissues, such as the trabecular meshwork (TM). Relentless efforts have been made on improving ocular drug bioavailability through either increasing drug residence time or modulation of corneal epithelia, but without significant success. Since direct and non-invasive assessments of human ocular bioavailability are practically impossible to date, there is no effective way to evaluate the effectiveness of different delivery strategies. A systematic study of drug transport across the major barriers in the eye may provide a better understanding of how these barriers affect drug transport and how they may be overcome to improve overall ocular drug bioavailability.; To this end, the transscleral and transcorneal permeability and diffusion coefficients of a potential TM drug, ethacrynic acid (ECA), were measured in ex vivo porcine eyes. The cytotoxicity of ECA on porcine corneal epithelial cells was also determined in vitro. A two-dimensional, axisymmetric mathematical model based on the anatomy of a human eye was also developed to simulate drug transport in the anterior chamber of the eye. A cellular pharmacokinetic and pharmacodynamic model is also developed to predict ECA toxicities for optimizing treatments of primary open-angle glaucoma (POAG).; In summary, the results indicated that increasing drug residence time in the precorneal region may have significant improvements on ocular drug bioavailability while modulation of corneal epithelia may have negligible effects. Although the majority of these data are for ECA, the models presented in this study, such as the binding-diffusion model, the ocular pharmacokinetic model for drug transport in the anterior chamber of the eye, and the cellular pharmacokinetic and pharmacodynamic model, can be used for evaluating other potential drugs as well. These models may also be useful for directing future delivery approaches to improve ocular bioavailability for treatments of diseases in the anterior chamber of the eye. |
