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Source: Ref. 10.

carries a net positive charge. As a result, a positively charged molecule can pass across the cornea more effectively at physiological pH (7.4).

The transcellular pathway is a path that a solute uses to diffuse through the apical lipid matrix of the epithelial membrane continuing through the cytoplasm and across the basolateral membrane. The ability of a solute to pass across the cell using this pathway depends on the interaction of the solute with plasma membrane components, e.g., lipids, cell surface receptors. For a molecule that adopts a passive transport mechanism, partitioning is a crucial step since this is a prerequisite for a molecule to enter the cell. As a result, the partition coefficient becomes a key factor in determining its transport across the epithelium. The optimum partition coefficients for corneal absorption has been reported to be in the range of 10-100 (12), indicating lipophilic molecules are preferred. However, other factors such as size, charge, etc. may also play a role. Theoretically, a small and lipophilic molecule can pass across the cornea effectively. However, this may not always be the case, as can be easily understood when the histology of the cornea is taken into account. The cornea is composed of three layers (Fig. 4) (8). The outermost layer is the epithelium, which is lipophilic in nature and has tight junctions. The middle layer is an acellular matrix, which contains about 85% water and is therefore hydrophilic in nature.

Figure 4 A simplified diagram of histology of the cornea. (Modified from Ref. 8.)

The innermost layer is the endothelium. Although the endothelium is lipophilic, it is leaky and does not give any significant resistance to the transport of molecules. It is believed that the epithelium provides the major resistance for hydrophilic/charged molecules and gives minimal resistance to small lipophilic molecules. However, after passing across the epithelium, further movement of these lipophilic molecules is limited by the matrix, which is hydrophilic in nature. As a result, in order to pass across the whole cornea, the molecule has to have a balance between its lipophilic and hydrophilic character.

Other transport mechanisms such as carrier-mediated transport, endo-cytosis, etc. may also be involved in transcellular transport but they are poorly understood.

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