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S. P. Srinivas, A. Chauhan, C. Gupta; Kinetics of Drug Penetration Across the Cornea at a Microscopic Level. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2420.
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Topical drugs access the anterior chamber of the eye mainly through transport across the cornea. In this study, we have examined the kinetics of penetration of a fluorescent compound applied topically. The resulting transcorneal transport profiles have been employed to develop a mechanistic model governing the topical pharmacokinetics.
The transient concentration vs. depth profiles of a hydrophobic dye, Rhodamine B (RhB; MW: 479), across rabbit corneas mounted in vitro were measured after topical application using a custom-built confocal microscope (at a depth resolution of at least 8 µm using a 40x water immersion objective of 0.75 NA). These profiles formed the basis for construction of a multi-scale non-compartmental pharmacokinetic model.
After topical administration, RhB distribution across the cornea showed discontinuities at the cellular boundaries. Specifically, RhB fluorescence was elevated in the lipophilic cellular layers relative to the hydrophilic stroma. The discontinuities indicate that conventional pharmacokinetic models, which model the entire cornea as a single compartment, are not suitable to describe RhB kinetics. This led to a model consisting diffusive transport across the epithelium, stroma, and endothelium. Parameter estimation by least-square minimization and their subsequent sensitivity analysis showed that the model can predict the observed transcorneal profiles.
Conventional approaches using compartmental models cannot adequately describe the transcorneal penetration of lipophilic drugs. The transport of lipophilic drugs across the epithelial layer is limited by slow partitioning from the bilayers into the internal cellular components.
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