Routes of Transport

Across any continuous epithelium, a solute can be transported either through the cells or between the cells. The cellular pathway is known as the transcel-lular route, and the intercellular pathway is known as the paracellular route (Fig. 2). The transport of most of the solutes is contributed by both pathways. Lipophilic molecules and molecules with specialized transport processes prefer the transcellular route, whereas hydrophilic molecules lacking membrane transport processes prefer the paracellular route. However, dissecting the fraction contributed by each pathway is difficult (Ho et al., 1999). One measure of the overall barrier permeability is its electrical resistance, a measure of the resistance of the tissue to ion transport. The electrical resistance of various ocular barriers is summarized in Table 1.

The mechanisms of transcellular transport include simple diffusion, facilitated diffusion, active transport, and endocytosis. The plasma membrane of a cell consists of a lipid bilayer with an array of peripherally and integrally associated proteins, some of which serve as specific transporters or

Efflux influx

Efflux influx

Figure 2 Transcellular and paracellular pathways for drug transport across epithelial and endothelial barriers.

receptors, which allow solute uptake into the cell via active transport, facilitated diffusion, or receptor-mediated endocytosis. However, for a majority of the currently available drug molecules, no such transporters or receptors exist, and these drugs are transported by passive diffusion through the apical membrane, through the cell proper, and across the baso-lateral membrane to move across the cell. During transcellular movement, the solute must interact with some components of the cell membrane. The interaction of the solute with the cell is influenced by both the structural characteristics of the solute and the cell itself.

Transport along the paracellular route is passive and is only limited by the size and charge of the intercellular spaces. The paracellular pathway is an aqueous route involving diffusion of the solute between adjacent epithelial cells/endothelial cells restricted by the presence of a series of junctional strands known as tight junctions or zonula occludens (ZO), which are joined at the apical pole (Madara and Trier, 1982; Yu, 2000). Freeze-fracture electron microscopy studies demonstrated that ZO forms fusion sites that appear as a complex network of protein strands that seal the intercellular

Table 1 Transmembrane Electrical Resistances of Various Ocular Barriers

Tissue

Ref.

Cornea

Intact rabbit cornea

Primary rabbit corneal epithelial cultures (air interface)

Ciliary body

Intact rabbit ciliary body Rabbit nonpigmented epithelial cell cultures

Human nonpigmented epithelial cell culture

Conjunctiva

Excised rabbit conjunctiva Primary rabbit conjunctival cultures (liquid interface) Primary rabbit conjunectival cultures (air interface)

Retina

RPE-Choroid

Adult human Fetal human Bovine Rabbit Cat

Cultured RPE

Fetal human Fetal bovine Adult human

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