Comparison of Drug Permeabilities Across the Blood–Retinal Barrier, Blood–Aqueous Humor Barrier, and Blood–Brain Barrier

Drugs vary in their ability to permeate the blood–retinal barrier (BRB), blood–aqueous humor barrier (BAB), and blood–brain barrier (BBB) and the factors affecting the drug permeation remain unclear. In this study, the permeability of various substances across BRB, BAB, and BBB in rats was determined using the brain uptake index (BUI), retinal uptake index (RUI), and aqueous humor uptake index (AHUI) methods. Lipophilic substances showed high permeabilities across BBB and BRB. The RUI values of these substances were approximately four-fold higher than the BUI values. The AHUI versus lipophilicity curve had a parabolic shape with AHUImax values at log D7.4 ranging from −1.0 to 0.0. On the basis of the difference on the lipophilicities, verapamil, quinidine, and digoxin showed lower permeability than predicted from those across BBB and BRB, whereas only digoxin showed a lower permeability across BRB. These low permeabilities were significantly increased by P-glycoprotein inhibitors. Furthermore, anion transporter inhibition increased the absorption of digoxin to permeate into the retina and aqueous humor. In conclusion, this study suggests that efflux transport systems play an important role in the ocular absorption of drugs from the circulating blood after systemic administration. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3904–3911, 2011