Lipophilicity and Transporter Influence on Blood-Retinal Barrier Permeability: A Comparison with Blood-Brain Barrier Permeability

Abstract

To determine the lipophilicity trend line from the relationship between the blood-retinal barrier (BRB) permeability and the lipophilicity of permeants and compare it with that of the blood-brain barrier (BBB). The retinal (RUI) and brain uptake index (BUI) of 26 radiolabeled compounds across the rat BRB and BBB, respectively, were measured using the carotid artery injection method. RUI was determined using 13 compounds expected to be transported from blood to the retina by passive diffusion and with a log n-octanol/Ringer distribution coefficient (DC) ranging from -2.56 to 2.48. The RUI values were correlated with the log of the DC [RUI = 46.2 × exp (0.515 × log DC), r(2) = 0.807]. A similar trend was obtained between BUI and lipophilicity. The RUI value for substrates of the influx transporters and P-glycoprotein (P-gp) was greater and smaller than the lipophilicity trend line, respectively. In contrast, [(3)H]verapamil, which is a substrate of P-gp, has a greater RUI value than the lipophilicity trend line, but not for BUI, suggesting that the BRB has an influx transport system for verapamil. The lipophilicity trend line constructed from the RUI and DC values is considered to reflect the transport properties of drugs undergoing passive diffusion across the BRB.