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R. Mutharasan, P. Kambadur, S.P. Srinivas; Calculation of Bioavailability Using Distributed Parameter Models of Trans-Corneal Transport . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4451.
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Purpose: Topical drugs applied on the ocular surface access the interior of the eye mainly through transport across the cornea. Given the structure of the cornea as a trilaminate, it is possible to optimize lipophilicity of drugs (characterized by octanol:water partition coefficient, denoted by PC) for enhanced bioavailability in the anterior chamber. In this study, we have calculated the bioavailability of topical drug analogs using a theoretical model of drug penetration across the cornea. Methods: Experimental data were gathered using a confocal microfluorometer (Srinivas and Maurice, 1992) from rabbit corneas mounted in vitro. Specifically, rhodamine B (RhB; PC = 270), fluorescein (F; PC = 0.6), and carboxyfluorescein (CF; PC = 0.0007) were used as fluorescent drug analogs. A mathematical model in the form of unsteady state reaction-diffusion equations was developed to describe the transient diffusion, partitioning, binding, and paracellular transport of the analogs across the three layers of the cornea. The model was simulated using MATLAB/FEMLAB finite elements software package to fit the experimental data and to determine flux at endothelial boundary. Results: Apparent concentration of CF in the epithelium was negligible even after 2 hours of exposure to CF at the anterior chamber. F, also applied at the anterior chamber accumulated significantly in the epithelium. RhB, being highly lipophilic, could be applied topically. This resulted in a significant accumulation in the epithelium and endothelium. Our model, which focused on RhB penetration, also predicted bioavailability in the anterior chamber consistent with reported data. Specifically, we modeled a topical drop of RhB (16% per minute decay on the ocular surface) and dilution in the anterior chamber (a/c volume = 250 microlitres, 2.5 microlitres per minute of aqueous flow). This simulation showed a logarithmic drop in mass of RhB in the cornea over a period of 3 hours. The concentration in the anterior chamber showed a peak at 90 minutes. These results are consistent with previous experimental reports on RhB penetration accross the cornea. Conclusions: The distributed parameter model can be verified through results reported previously for F, CF and RhB. The validated model will potentailly provide additional insights into transport across the cornea and enable optimization of PC.
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