Influence of lipophilicity on drug partitioning into sclera, choroid-retinal pigment epithelium, retina, trabecular meshwork, and optic nerve.

In vitro bovine eye tissue/phosphate-buffered saline, pH 7.4, partition coefficients (Kt:b), in vitro binding to natural melanin, and in vivo delivery at 1 h after posterior subconjunctival injection in Brown Norway rats were determined for eight beta-blockers. The Kt:b was in the order intact tissue, dry weight method >or= intact tissue, wet weight method corrected for tissue water and drug in tissue water >> intact tissue, wet weight method > homogenized tissue. In intact tissue methods, Kt:b followed the order choroid-retinal pigment epithelium (RPE) > trabecular meshwork > retina > sclera approximately optic nerve; propranolol > betaxolol > pindolol approximately timolol approximately metoprolol > sotalol approximately atenolol approximately nadolol. Intact tissue, wet weight log (Kt:b) correlated positively with log D for all tissues (R(2) of 0.7-0.9). Log (melanin binding capacity) correlated positively with choroid-RPE log (Kt:b) (R(2) of 0.5). With an increase in concentration, Kt:b decreased in trabecular meshwork for all beta-blockers and for some lipophilic beta-blockers in choroid-RPE and sclera. With an increase in drug lipophilicity, in vivo tissue distribution increased in choroid-RPE, iris-ciliary body, sclera, and cornea but exhibited a declining trend in retina, vitreous, and lens. In vitro bovine intact tissue, wet weight Kt:b correlated positively with rat in vivo tissue/vitreous humor distribution for sclera, choroid-RPE, and retina (R(2) of 0.985-0.993). In vitro tissue partition coefficients might be useful in predicting in vivo drug distribution after trans-scleral delivery. Less lipophilic solutes exhibiting limited nonproductive binding in choroid-RPE might exhibit greater trans-scleral delivery to the retina and vitreous.