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J-EC Lin, VH L Lee; Predicting Ocular Drug Absorption Using a Functional Primary Culture of Rabbit Corneal Epithelial Cell Layers Model . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1675.
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Purpose: To determine whether a functional primary culture of rabbit corneal epithelial cell layers model (RCrECL) can be used for predicting ocular drug absorption. Methods: Model compounds of varying molecular size, lipophilicity, and transport mechanism were used, including beta adrenergic antagonists, mannitol, cidofovir, acyclovir, lactic acid, guanidine, gly-sar, valacyclovir, verapamil, L-carnitine, uridine and cyclosporinA (CsA). RCrECL was used to determine the in-vitro apparent drug permeability coefficients (Papp) of the model drugs. The % absorbed of a topically applied 25 ml dose of a drug solution in the rabbit eye at 30 min post-dosing was used as an index of ocular drug absorption. Depending on the compound, the assay was either RP-HPLC under isocratic conditions or radiometric analysis. Results: The Papp of all the compounds (n=23) evaluated fell within the range of 0.05 ± 0.008x10-6 cm/sec (mannitol) and 12.9 ± 0.05x10-6 cm/sec (betaxolol). The corresponding % dose absorbed was in the range of 0.0058 ± 0.0016% (mannitol) and 5.95 ± 0.85% (CsA), with betaxolol being the fourth highest. A good in-vitro/in-vivo correlation was observed (y=0.049+0.052x, r2=0.94, n=23), except for the actively transported CsA (a Pgp substrate), uridine (a nucleoside transporter substrate) and L-carnitine (an organic cation transporter substrate). The ocular absorption of these three compounds was underestimated according to the above correlation equation. They appeared to follow their own correlation (y=0.814+12.214x, r2=1, n=3). Conclusion: RCrECL appears to be a good in-vitro model for predicting ocular drug absorption. Knowledge of the underlying transport mechanism is, however, required to select the correlation equation to be used. (Supported in part by EY12356).
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