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RK Mutharasan, R Mutharasan, SP Srinivas; A Non-compartmental Model For Transport Of Rhodamine B Across Rabbit Cornea Mounted In Vitro . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3876.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To characterize the partitioning and diffusion of Rhodamine B (RhB; a fluorescent lipophilic molecule) across the cornea for gaining insights into pharmacokinetics of lipophilic drugs administered topically on the eye surface. Methods: A mathematical model describing the transient diffusion through the three layers, epithelium, stroma, and endothelium, was modeled by partial differential equations. The model includes the partitioning, reversible binding kinetics, and diffusion of RhB. The parameters of the model consisted of partition coefficients (PCs), binding rate constant, binding equilibrium constant, and diffusion coefficients for each of the three layers. Experimental data gathered previously (Srinivas and Maurice, ARVO, 1992) from rabbit corneas mounted in vitro were employed for parameter estimation. Results: RhB fluorescence increased rapidly in the epithelium after exposure to Ringers containing RhB and then reached a steady state. Extrapolation of this profile to zero time identified the concentration of RhB in the epithelium that is in equilibrium with RhB in the Ringers. PC of RhB was thus calculated. The rate of increase in RhB fluorescence was used to determine the binding rate constant for the epithelial layer. From the same profile, the steady state value of the fluorescence equilibrium-binding constant for the epithelial layer was determined. These constants were then assumed to be same for the other cellular layer, the endothelium. PC of the stroma (≷80% water), however, was taken as the inverse of its value determined for the epithelial layer. Initial estimates of the diffusion coefficients for RhB in the stroma and cellular layers were taken from the published values. The remaining two parameters in the model (viz., the two binding rate and equilibrium constants for the stroma) were varied to fit the experimental transcorneal fluorescence profiles. Simulation of the model with the estimated parameter set was found to to be comparable to transcorneal RhB profiles determined experimentally. Conclusion: (1) Conventional approaches using compartment models cannot adequately describe the mechanistic details of transcorneal penetration of lipophilic drugs. (2) A «Dissolve-Diffuse» mechanism framed independently for the three layers is necessary to describe the transcorneal penetration kinetics of RhB and other lipophilic compounds.
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