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.
Get full access to this article
View all access options for this article.
References
1.
IkunoY. Overview of the complications of high myopia. Retina, 2017; 37(12):2347–2351; doi: 10.1097/IAE.0000000000001489
2.
CooperJ, TkatchenkoAV. A review of current concepts of the etiology and treatment of myopia. Eye Contact Lens, 2018; 44(4):231–247; doi: 10.1097/ICL.0000000000000499
3.
JonesD, LuensmannD. The prevalence and impact of high myopia. Eye Contact Lens, 2012; 38(3):188–196; doi: 10.1097/ICL.0b013e31824ccbc3
VutipongsatornK, YokoiT, Ohno-MatsuiK. Current and emerging pharmaceutical interventions for myopia. Br J Ophthalmol, 2019; 103(11):1539–1548; doi: 10.1136/bjophthalmol-2018-313798
6.
OhDJ, ChenJL, VajaranantTS, et al.Brimonidine tartrate for the treatment of glaucoma. Expert Opin Pharmacother, 2019; 20(1):115–122; doi: 10.1080/14656566.2018.1544241
7.
KusariJ, PadilloE, ZhouSX, et al.Effect of brimonidine on retinal and choroidal neovascularization in a mouse model of retinopathy of prematurity and laser-treated rats. Invest Ophthalmol Vis Sci, 2011; 52(8):5424–5431; doi: 10.1167/iovs.10-6262
8.
KusariJ, ZhouSX, PadilloE, et al.Inhibition of vitreoretinal VEGF elevation and blood-retinal barrier breakdown in streptozotocin-induced diabetic rats by brimonidine. Invest Ophthalmol Vis Sci, 2010; 51(2):1044–1051; doi: 10.1167/iovs.08-3293
9.
Valiente-SorianoFJ, Ortín-MartínezA, Di PierdomenicoJ, et al.Topical Brimonidine or Intravitreal BDNF, CNTF, or bFGF Protect Cones Against Phototoxicity. Transl Vis Sci Technol, 2019; 8(6):36; doi: 10.1167/tvst.8.6.36
10.
LiuY, WangY, LvH, et al.α-adrenergic agonist brimonidine control of experimentally induced myopia in guinea pigs: A pilot study. Mol Vis, 2017; 23:785–798.
11.
CarrBJ, NguyenCT, StellWK. Alpha2 -adrenoceptor agonists inhibit form-deprivation myopia in the chick. Clin Exp Optom, 2019; 102(4):418–425; doi: 10.1111/cxo.12871
12.
YangY, WuJ, WuD, et al.Intravitreal brimonidine inhibits form-deprivation myopia in guinea pigs. Eye Vis (Lond), 2021; 8(1):27; doi: 10.1186/s40662-021-00248-0
13.
WangWY, ChenC, ChangJ, et al.Pharmacotherapeutic candidates for myopia: A review. Biomed Pharmacother, 2021; 133:111092; doi: 10.1016/j.biopha.2020.111092
14.
LinghamG, MackeyDA, LucasR, et al.How does spending time outdoors protect against myopia? A review. Br J Ophthalmol, 2020; 104(5):593–599; doi: 10.1136/bjophthalmol-2019-314675
15.
HuangD, ChenYS, RupenthalID. Overcoming ocular drug delivery barriers through the use of physical forces. Adv Drug Deliv Rev, 2018; 126:96–112; doi: 10.1016/j.addr.2017.09.008
16.
TamhaneM, LuuKT, AttarM. Ocular pharmacokinetics of brimonidine drug delivery system in monkeys and translational modeling for selection of dose and frequency in clinical trials. J Pharmacol Exp Ther, 2021; 378(3):207–214; doi: 10.1124/jpet.120.000483
17.
BeccariaM, CabooterD. Current developments in LC-MS for pharmaceutical analysis. Analyst, 2020; 145(4):1129–1157; doi: 10.1039/c9an02145k
BaiL, FeiQ, LeiF, et al.Comparative analysis of pharmacokinetics of vancomycin hydrochloride in rabbits after ocular, intragastric, and intravenous administration by LC-MS/MS. Xenobiotica, 2020; 50(12):1461–1468; doi: 10.1080/00498254.2020.1774681
20.
JinL, DingH, DegirmenciV, et al.Determination of the peptide AWRK6 in rat plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application to pharmacokinetics. Molecules, 2021; 27(1):92; doi: 10.3390/molecules27010092
21.
GeY, LiZ, ZhangL, et al.Pharmacokinetics and tissue distribution study of bisabolangelone from Angelicae Pubescentis Radix in rat using LC-MS/MS. Biomed Chromatogr, 2019; 33(3):e4433; doi: 10.1002/bmc.4433
22.
SiegwartJT Jr, NortonTT. The time course of changes in mRNA levels in tree shrew sclera during induced myopia and recovery. Invest Ophthalmol Vis Sci, 2002; 43(7):2067–2075.
23.
ShinnoK, KurokawaK, KozaiS, et al.The relationship of brimonidine concentration in vitreous body to the free concentration in retina/choroid following topical administration in pigmented rabbits. Curr Eye Res, 2017; 42(5):748–753; doi: 10.1080/02713683.2016.1238941
24.
AcheampongAA, ShackletonM, JohnB, et al.Distribution of brimonidine into anterior and posterior tissues of monkey, rabbit, and rat eyes. Drug Metab Dispos, 2002; 30(4):421–429; doi: 10.1124/dmd.30.4.421
25.
TroiloD, SmithEL 3rd, NicklaDL, et al.IMI - report on experimental models of emmetropization and myopia. Invest Ophthalmol Vis Sci, 2019; 60(3):M31–M88; doi: 10.1167/iovs.18-25967
26.
DumouchelJL, ChemuturiN, MiltonMN, et al.Models and approaches describing the metabolism, transport, and toxicity of drugs administered by the ocular route. Drug Metab Dispos, 2018; 46(11):1670–1683; doi: 10.1124/dmd.118.082974
27.
Del AmoEM, UrttiA. Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data [published correction appears in Exp Eye Res 2018;169:60]. Exp Eye Res, 2015; 137:111–124; doi: 10.1016/j.exer.2015.05.003
28.
AgrahariV, MandalA, AgrahariV, et al.A comprehensive insight on ocular pharmacokinetics. Drug Deliv Transl Res, 2016; 6(6):735–754; doi: 10.1007/s13346-016-0339-2
29.
TakamuraY, TomomatsuT, MatsumuraT, et al.Vitreous and aqueous concentrations of brimonidine following topical application of brimonidine tartrate 0.1% ophthalmic solution in humans. J Ocul Pharmacol Ther, 2015; 31(5):282–285; doi: 10.1089/jop.2015.0003
30.
TorisCB, GleasonML, CamrasCB, et al.Effects of brimonidine on aqueous humor dynamics in human eyes. Arch Ophthalmol, 1995; 113(12):1514–1517; doi: 10.1001/archopht.1995.01100120044006
31.
WenR, ChengT, LiY, et al.Alpha 2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage. J Neurosci, 1996; 16(19):5986–5992; doi: 10.1523/JNEUROSCI.16-19-05986.1996
32.
HongS, HanSH, KimCY, et al.Brimonidine reduces TGF-beta-induced extracellular matrix synthesis in human Tenon's fibroblasts. BMC Ophthalmol, 2015; 15:54; doi: 10.1186/s12886-015-0045-8
33.
KusakariT, SatoT, TokoroT. Visual deprivation stimulates the exchange of the fibrous sclera into the cartilaginous sclera in chicks. Exp Eye Res, 2001; 73(4):533–546; doi: 10.1006/exer.2001.1064
34.
RohrerB, StellWK. 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. Exp Eye Res, 1994; 58(5):553–561; doi: 10.1006/exer.1994.1049
35.
SekoY, ShimokawaH, TokoroT. Expression of bFGF and TGF-beta 2 in experimental myopia in chicks. Invest Ophthalmol Vis Sci, 1995; 36(6):1183–1187.
36.
ThomsonK, KellyT, KaroutaC, et al.Insights into the mechanism by which atropine inhibits myopia: Evidence against cholinergic hyperactivity and modulation of dopamine release. Br J Pharmacol, 2021; 178(22):4501–4517; doi: 10.1111/bph.15629
37.
ThomsonK, KaroutaC, AshbyR. Form-deprivation and lens-induced myopia are similarly affected by pharmacological manipulation of the dopaminergic system in chicks. Invest Ophthalmol Vis Sci, 2020; 61(12):4; doi: 10.1167/iovs.61.12.4
38.
MathisU, FeldkaemperM, WangM, et al.Studies on retinal mechanisms possibly related to myopia inhibition by atropine in the chicken. Graefes Arch Clin Exp Ophthalmol, 2020; 258(2):319–333; doi: 10.1007/s00417-019-04573-y
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
