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C. E. Schwartz, A. Savinainen, P. Gjorstrup; Resolvin Analogs With Pharmacokinetic Properties Suitable for Topical Administration to Treat Ocular Diseases. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3179.
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The resolvins constitute a group of endogenous small molecules formed by enzymatic oxidation of the omega-3 unsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid. Resolvins are highly potent and efficacious immune response regulators as shown in models of arthritis, colitis, and asthma, and they were recently shown to reduce vascular pathology in a model of oxygen-induced retinopathy. As mechanisms central to chronic inflammation may also be significant in ocular diseases, including dry eye, we examined prodrugs of resolvin analogs to assess their suitability for topical ocular administration.
Ester prodrugs were compared to parent carboxylic acids for their pharmacokinetic (PK) properties after topical administration to the rabbit eye. The following experimental design was used: at time zero rabbits were administered a single 30 µL drop of either a 30 µg/mL or 300 µg/mL drug concentration to the right and left eye, respectively. At each time point (15, 30, 60, 120, 360 min) two animals were euthanized, the right and left eye tissues separately dissected, frozen and stored for later measurement of drug levels.
Designing resolvin analog prodrugs by converting the parent carboxylic acid to methyl or isopropyl esters markedly improved ocular tissue penetration. For the parent compound RX-10008, corneal exposure increased ~10-fold when administered topically as prodrug. There was no difference in tissue uptake whether the prodrug was a methyl or isopropyl ester. Following administration of either ester prodrug, cleavage to active parent compound was rapid and at no time point could intact prodrug be measured. Drug half-life in cornea was ~1.5 hours with peak levels of ~4 ng/mg at 15 min. Administration of prodrug also led to significant enhancement of RX-10008 levels in the aqueous humor and vitreous with peak concentrations at ~1000 ng/mL and ~3 ng/mL, respectively. Kinetic properties were dose-independent and repeat administration twice a day for seven days did not show any accumulation of drug. The analogs were also well tolerated with no increase in Drazie scores.
We have demonstrated the feasibility of using an ester prodrug principle to enhance eye tissue penetration of a resolvin analog. In addition to obtaining pharmacologically relevant concentrations in corneal tissue, these analogs may also have unique PK properties making them suitable as eye drops for the treatment of retinal disease.
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