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Mayssa Attar, Moon Kim, George Sachs, David Scott, Craig B. Struble, Devin F. Welty; Modulation of Glucocorticoid Receptor Gene Expression: Potential Role in the Pharmacokinetic/Pharmacodynamic Relationship of Ozurdex. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5643.
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© ARVO (1962-2015); The Authors (2016-present)
To monitor changes in mRNA expression of the glucocorticoid receptor (GR) in retina, choroid-retinal pigment epithelium (RPE) and iris-ciliary body following a single administration of sustained-release dexamethasone (DEX) intravitreal implant (OzurdexTM; Allergan, Inc.) and investigate the role modulation of GR expression may play in the pharmacokinetic/pharmacodynamic relationship.
Ten male Macaca fascicularis received bilateral 0.7 mg DEX implants. Retina, choroid-RPE and iris-ciliary body samples were collected at predetermined intervals up to 270 days after administration. Gene expression was analyzed by real- time polymerase chain reaction (RT-PCR) using untreated monkey ocular tissues as a control. Based on RT-PCR results, microarray analyses were performed on select samples. To gain an understanding of the relevance of findings in monkeys to humans, ARPE-19 cells were treated with dexamethasone and GR gene expression was monitored.
Upregulation of GR gene expression was observed after dexamethasone treatment for up to 6 months in choroid-RPE but not retina or iris-ciliary body. On Day 7 GR gene expression was upregulated 3.3-fold and increased to an average of 36.8±22.0-fold up to 6 months. Upregulation of GR mRNA was greater than upregulation of CYP3A8 and P-gp mRNA in choroid-RPE. Of the greater than 40000 genes examined using microarray analysis in choroid-RPE samples collected on day 30 and compared to untreated choroid-RPE, 7595 genes show a greater than twofold change, with 4877 upregulated and 2718 downregulated. Expression of at least 7 genes directly related to GR activity was changed, 5 genes upregulated >2.2 to 3.3-fold and 2 genes downregulated >2.4 to 2.8-fold. GR expression was also upregulated in ARPE-19 cells treated with dexamethasone.
GR gene expression is upregulated in choroid-RPE in vivo following a single administration of sustained-release dexamethasone (DEX) intravitreal implant. Modulation of GR gene expression may underlie the mechanism by which high initial drug concentrations followed by a prolonged period of low concentrations are able to provide extended management of posterior segment disease.
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