The present data indicated that the brimonidine concentration in the vitreous body was comparable to the free concentration in the posterior retina/choroid. This suggests that the vitreous concentration can be a surrogate indicator of the free brimonidine concentration in the posterior retina/choroid. From the present findings, it is expected that multiple instillation of brimonidine tartrate ophthalmic solution may produce the sufficient free concentration for activation of the α-adrenergic receptor in the retina/choroid in human.

Introduction: This study was aimed to compare ocular tissue distribution and systemic exposure of brimonidine and timolol after single topical administration to rabbits of fixed-combination ophthalmic solution of 0.1% brimonidine tartrate and 0.5% timolol and single drugs (0.1% brimonidine tartrate ophthalmic solution or 0.5% timolol ophthalmic solution) or concomitant administration of single drugs. Methods: Rabbits were treated with a single topical administration of each ophthalmic solution or concomitant administration of single drugs. For concomitant administration, 0.1% brimonidine tartrate was administered after 0.5% timolol instillation successively within 10 s (without interval) or with 5-min intervals. Brimonidine and timolol concentrations in the aqueous humor, retina/choroid, vitreous body, and plasma were determined with liquid chromatography-tandem mass spectrometry.

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IntroductionAzithromycin demonstrates high tissue distribution and prolonged elimination half-life. In this study, we monitored the pharmacokinetics of a single ophthalmic administration of 1% azithromycin ophthalmic solution containing polycarbophil in the extraocular tissues, including the eyelid, and compared it with that of two commercial ophthalmic products, 1.5% levofloxacin ophthalmic solution and 0.3% ofloxacin ophthalmic ointment.MethodsRabbits were treated with either a single topical administration of 1% azithromycin ophthalmic solution, 1.5% levofloxacin ophthalmic solution, or 0.3% ofloxacin ophthalmic ointment. The eyelid, conjunctiva, and cornea were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 h post-administration. Tissue samples were pretreated for drug concentration measurements by ultra-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined by non-compartmental analysis.ResultsAzithromycin was rapidly absorbed, and its levels remained near the observed maximum concentrations for up to 24 h post-administration in all tissue. In contrast, extraocular tissue concentrations of levofloxacin and ofloxacin decreased with time. The maximum concentrations of azithromycin, levofloxacin, and ofloxacin were 35.6, 34.1, and 55.1 µg/g in the eyelid, 44.2, 46.8, and 20.4 µg/g in the conjunctiva, and 79.9, 18.0, and 2.21 µg/g in the cornea, respectively. The values of the area under the curve from 0 to 24 h after administration of azithromycin, levofloxacin, and ofloxacin were 602, 58.5, and 267 µg·h/g in the eyelid, 837, 43.2, and 51.9 µg·h/g in the conjunctiva, and 1250, 26.4, and 5.46 µg h/g in the cornea, respectively.ConclusionThe drug concentrations of azithromycin and levofloxacin were relatively comparable among the extraocular tissues following topical administration of the respective ophthalmic solutions, whereas the concentrations of ofloxacin varied following dosing of its ophthalmic ointment. The slow elimination profile in any extraocular tissue of rabbits was unique to azithromycin, and led to the demonstration of high exposures of azithromycin in all extraocular tissues after ophthalmic administration.FundingThis research and Rapid Service Fees were supported by Senju Pharmaceutical Co., Ltd.

Introduction Brimonidine bioavailability in the aqueous humor depends on the solution pH following topical administration. The purpose of this study was to investigate the effect of solution pH on brimonidine distribution in the posterior ocular tissues in pigmented rabbits. Methods The anterior retina/choroid, posterior retina/choroid, and vitreous body of pigmented rabbits were collected 0.67, 1.5, 3, 6, 12, 24, 168, and 360 h after the administration of a single topical dose of 0.2% brimonidine tartrate ophthalmic solution, pH 6.4 (Alphagan ® ; Allergan Inc., Irvine, CA, USA). Brimonidine concentrations in these tissues were quantified using liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters were determined using noncompartmental analysis, and the results were compared with tissues from eyes administered 0.1% brimonidine tartrate ophthalmic solution, pH 7.3 (Aiphagan ® ; Senju Pharmaceutical Co., Ltd., Osaka, Japan) in our previous study conducted using the same procedure. Results Topically applied brimonidine was distributed rapidly into the posterior tissues of the eye after a single ophthalmic administration of the 0.2% ophthalmic solution. The areas under the curve from time 0 to 360 h following dosing with the 0.2% ophthalmic solution were 500,000, 14,300, and 28.7 ng h/g in the anterior and posterior retina/choroid, and vitreous body, respectively. Conclusion The differences in the areas under the curve between two ophthalmic solutions were less than the difference in drug concentrations between these two products in any tissues. This finding indicates that the change in the solution pH from 6.4 to 7.3 increases brimonidine bioavailability into the posterior ocular tissues similarly as into the aqueous humor. Funding Senju Pharmaceutical Co., Ltd.