Abstract
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 β-blockers. The Kt:b was in the order intact tissue, dry weight method ≥ 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 ∼ optic nerve; propranolol > betaxolol > pindolol ∼ timolol ∼ metoprolol > sotalol ∼ atenolol ∼ 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 β-blockers and for some lipophilic β-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.
Footnotes
- Received September 11, 2009.
- Accepted November 18, 2009.
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This work was supported by National Institutes of Health National Eye Institute [Grant EY017533]; and by an unrestricted research gift from Pfizer Global Research.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.161570.
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ABBREVIATIONS:
- RPE
- retinal pigment epithelium
- PBS
- phosphate-buffered saline
- DC
- distribution coefficient
- LC-MS/MS
- liquid chromatography/tandem mass spectrometry
- BN
- Brown Norway.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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