P-gp, a 170 kDa membrane glycoprotein, is expressed in tumor cells as well as various normal tissues associated with the eye, small intestine, liver, kidney, lung, and the blood-brain barrier (Thiebaut et al., 1989). In the eye, P-gp is expressed in retinal capillary endothelial cells, iris, and ciliary muscle cells (Holash and Stewart, 1993), and retinal pigmented (Schlingemann et al., 1998), ciliary nonpigmented (Wu et al., 1996), corneal (Kawazu et al., 1999), and conjunctival epithelial (Saha et al., 1998) cells. Pgp exports a variety of structurally and pharmacologically unrelated hydro-phobic compounds such as vinblastine, vincristine, cyclosporin (CsA), glucocorticoids, and lipophilic peptides such as N-acetyl-leucyl-leucyl-norleucinal (Sharma et al., 1991; Hunter et al., 1991, Tsuji et al., 1992).
Rhodamine-123 (Rho-123), a flourescent P-gp substrate, is often used to examine the function of P-gp in vitro and in vivo. Kajikawa et al. (1999) determined the contribution of P-gp to rabbit blood-aqueous barrier by analyzing the distribution of Rho-123 in aqueous humor after intravenous injection in the presence or absence of topically administered P-gp inhibitors. Following topical quinidine (12.5 mM eye drops, five applications at 5-minute intervals) and cyclosporin A (12.5 mM eye drops, five applications at 5-minute intervals) treatments, the aqueous humor distribution of intravenously injected Rho-123 was increased 11.2- and 11.3-fold, respectively, compared to controls. This suggests that P-gp is functionally active in the blood-aqueous barrier. Functional studies with other P-gp substrates, such as cyclosporin A, verapamil, and dexamethasone, were also investigated to determine the presence of P-gp activity in the conjunctival epithelium (Saha et al., 1998). The basolateral-apical apparent permeability coefficients of cyclosporin A, verapmil, and dexamethasone were 9.3, 3.4, and 1.6 times that of apical-basolateral permeability coefficients, respectively. Cyclosporin A efflux was reduced by 50-70% in the presence of verapamil and anti-Pgp antibody (4E3 mAb), consistent with P-gp activity in the conjunctival epithelium.
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