Ocular Posterior Segment Distribution and Pharmacokinetics of Brimonidine After Intravitreal Administration in Guinea Pigs.

Purpose: Brimonidine is a highly alpha-2 adrenergic agonist, which provides a potential myopia control effect. This study aimed to examine the pharmacokinetics and concentration of brimonidine in the posterior segment tissue of eyes in guinea pigs. Methods: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was successfully used for brimonidine pharmacokinetics and tissue distribution research in guinea pigs following intravitreal administration (20 μg/eye). Results: Brimonidine concentrations in the retina and sclera were maintained at a high level (>60 ng/g) at 96 h postdosing. Brimonidine concentration peaked in the retina (377.86 ng/g) at 2.41 h and sclera (306.18 ng/g) at 6.98 h. The area under curve (AUC0-∞) was 27,179.99 ng h/g in the retina and 39,529.03 ng h/g in the sclera. The elimination half-life (T1/2e) was 62.43 h in the retina and 67.94 h in the sclera. Conclusions: The results indicated that brimonidine was rapidly absorbed and diffused to the retina and sclera. Meanwhile, it maintained higher posterior tissue concentrations, which can effectively activate the alpha-2 adrenergic receptor. This may provide pharmacokinetic evidence for the inhibition of myopia progression by brimonidine in animal experiments.

[1]  Haibo Ding,et al.  Determination of the Peptide AWRK6 in Rat Plasma by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) and Its Application to Pharmacokinetics , 2021, Molecules.

[2]  R. Ashby,et al.  Insights into the mechanism by which atropine inhibits myopia: evidence against cholinergic hyperactivity and modulation of dopamine release , 2021, British journal of pharmacology.

[3]  X. Zhong,et al.  Intravitreal brimonidine inhibits form-deprivation myopia in guinea pigs , 2021, Eye and Vision.

[4]  M. Attar,et al.  Ocular Pharmacokinetics of Brimonidine Drug Delivery System in Monkeys and Translational Modeling for Selection of Dose and Frequency in Clinical Trials , 2021, The Journal of Pharmacology and Experimental Therapeutics.

[5]  C. Pang,et al.  Pharmacotherapeutic candidates for myopia: A review. , 2021, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[6]  R. Ashby,et al.  Form-Deprivation and Lens-Induced Myopia Are Similarly Affected by Pharmacological Manipulation of the Dopaminergic System in Chicks , 2020, Investigative ophthalmology & visual science.

[7]  Q. Ma,et al.  Comparative analysis of pharmacokinetics of vancomycin hydrochloride in rabbits after ocular, intragastric, and intravenous administration by LC-MS/MS , 2020, Xenobiotica; the fate of foreign compounds in biological systems.

[8]  D. Cabooter,et al.  Current developments in LC-MS for pharmaceutical analysis. , 2020, The Analyst.

[9]  F. Schaeffel,et al.  Studies on retinal mechanisms possibly related to myopia inhibition by atropine in the chicken , 2019, Graefe's Archive for Clinical and Experimental Ophthalmology.

[10]  D. Mackey,et al.  How does spending time outdoors protect against myopia? A review , 2019, British Journal of Ophthalmology.

[11]  L. Wheeler,et al.  Topical Brimonidine or Intravitreal BDNF, CNTF, or bFGF Protect Cones Against Phototoxicity , 2019, Translational vision science & technology.

[12]  K. Ohno-Matsui,et al.  Current and emerging pharmaceutical interventions for myopia , 2019, British Journal of Ophthalmology.

[13]  Lisa A. Ostrin,et al.  IMI – Report on Experimental Models of Emmetropization and Myopia , 2019, Investigative ophthalmology & visual science.

[14]  W. Stell,et al.  Alpha2‐adrenoceptor agonists inhibit form‐deprivation myopia in the chick , 2019, Clinical & experimental optometry.

[15]  Xiumei Gao,et al.  Pharmacokinetics and tissue distribution study of bisabolangelone from Angelicae Pubescentis Radix in rat using LC-MS/MS. , 2018, Biomedical chromatography : BMC.

[16]  Judy L. Chen,et al.  Brimonidine tartrate for the treatment of glaucoma , 2018, Expert opinion on pharmacotherapy.

[17]  V. Sasseville,et al.  Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route , 2018, Drug Metabolism and Disposition.

[18]  Di Huang,et al.  Overcoming ocular drug delivery barriers through the use of physical forces , 2017, Advanced drug delivery reviews.

[19]  H. Tokushige,et al.  The Relationship of Brimonidine Concentration in Vitreous Body to the Free Concentration in Retina/Choroid Following Topical Administration in Pigmented Rabbits , 2017, Current eye research.

[20]  Animikh Ray,et al.  A comprehensive insight on ocular pharmacokinetics , 2016, Drug Delivery and Translational Research.

[21]  A. Urtti,et al.  Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data. , 2015, Experimental eye research.

[22]  Samin Hong,et al.  Brimonidine reduces TGF-beta-induced extracellular matrix synthesis in human Tenon’s fibroblasts , 2015, BMC Ophthalmology.

[23]  Y. Le,et al.  Effect of brimonidine on retinal and choroidal neovascularization in a mouse model of retinopathy of prematurity and laser-treated rats. , 2011, Investigative ophthalmology & visual science.

[24]  C. Wildsoet,et al.  Pharmaceutical intervention for myopia control , 2010, Expert review of ophthalmology.

[25]  J. Kusari,et al.  Inhibition of vitreoretinal VEGF elevation and blood-retinal barrier breakdown in streptozotocin-induced diabetic rats by brimonidine. , 2010, Investigative ophthalmology & visual science.

[26]  L. Wheeler,et al.  Distribution of brimonidine into anterior and posterior tissues of monkey, rabbit, and rat eyes. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[27]  Tetsuji Sato,et al.  Visual deprivation stimulates the exchange of the fibrous sclera into the cartilaginous sclera in chicks. , 2001, Experimental eye research.

[28]  M. Yablonski,et al.  Effects of brimonidine on aqueous humor dynamics in human eyes. , 1995, Archives of ophthalmology.

[29]  W. Stell,et al.  Basic fibroblast growth factor (bFGF) and transforming growth factor beta (TGF-beta) act as stop and go signals to modulate postnatal ocular growth in the chick. , 1994, Experimental eye research.

[30]  Y. Takamura,et al.  Vitreous and aqueous concentrations of brimonidine following topical application of brimonidine tartrate 0.1% ophthalmic solution in humans. , 2015, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.