Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration
Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration
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DOI：
10.1023/b:pham.0000045231.51924.e8
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发表时间：
2004-10-01
影响因子：
3.7
通讯作者：
Kompella, UB
中科院分区：
文献类型：
--
作者：
Ayalasomayajula, SP;Kompella, UB
目的。我们先前已经证明，塞来昔布是一种选择性的COX-2抑制剂，在反复口服后可以到达视网膜，并在大鼠模型中抑制糖尿病诱导的血管内皮生长因子(VEGF)mRNA的表达和血管渗漏。本研究的目的是量化塞来昔布经结膜下途径与全身途径的视网膜相对生物利用度。在雄性SD大鼠结膜下和腹腔注射3 mg/只的药物混悬液后，测定了塞来昔布的血浆和眼组织分布。分别于给药后0.5h、1h、2h、3h、4h、8h、12h处死动物，采血，眼球摘除冰冻。分离血浆、巩膜、视网膜、玻璃体、晶状体和角膜，用高效液相色谱法测定塞来昔布浓度。药物的组织暴露被测量为药物浓度-时间分布曲线下的面积(AUC(0-无穷))。相对生物利用度以结膜下组和腹膜内组之间的AUC(0-无穷大)比率来评估。对于同侧结膜下给药眼，血浆、巩膜、视网膜、玻璃体、晶状体和角膜的AUC(0-无穷大)比分别为0.8+/-0.1、53+/-4、54+/-8、145+/-21、61+/-16和52+/-6。对侧眼组织中，巩膜、视网膜、玻璃体、晶状体和角膜的AUC(0-无穷大)比值分别为1.2×0.3、1.1×0.3、1.1×0.4、1.0×0.3和1.2×0.3。假设对侧眼的药物AUC与同侧眼的全身途径对AUC的贡献相等，则局部途径而不是全身循环对塞来昔布输送到同侧眼组织的贡献率估计为98%或更高。与腹膜内给药相比，结膜下给药后塞来昔布的视网膜释放显著增加。经巩膜途径几乎完全解释了结膜下给药后塞来昔布的视网膜给药。
Purpose. We have previously demonstrated that celecoxib, a selective COX-2 inhibitor, reaches the retina following repeated oral administrations and inhibits diabetes-induced vascular endothelial growth factor (VEGF) mRNA expression and vascular leakage in a rat model. The aim of this study was to quantify the relative retinal bioavailability of celecoxib from the subconjunctival route compared to a systemic route.Methods. The plasma and ocular tissue distribution of celecoxib was determined in male Sprague-Dawley rats following subconjunctival and intraperitoneal administrations of drug suspension at a dose of 3 mg/rat. The animals were sacrificed at 0.5, 1, 2, 3, 4, 8, and 12 h post-dosing, the blood was collected, and the eyes were enucleated and frozen. The plasma, sclera, retina, vitreous, lens, and the cornea were isolated and celecoxib levels were determined using an HPLC method. The tissue exposure of the drug was measured as the area under the curve (AUC(0-infinity)) of the concentration vs. time profiles. The relative bioavailability was estimated as the AUC(0-infinity) ratio between subconjunctival and intraperitoneal groups.Results. For the subconjunctivally dosed (ipsilateral) eye, the AUC(0-infinity) ratios between subconjunctival and intraperitoneal groups were 0.8 +/- 0.1, 53 +/- 4, 54 +/- 8, 145 +/- 21, 61 +/- 16, and 52 +/- 6 for plasma, sclera, retina, vitreous, lens, and cornea, respectively. For the contralateral ocular tissues, the AUC(0-infinity) ratios were 1.2 infinity 0.3, 1.1 infinity 0.3, 1.1 +/- 0.4, 1.0 +/- 0.3, and 1.2 +/- 0.3 in the sclera, retina, vitreous, lens, and the cornea, respectively, between the subconjunctival and the intraperitoneal groups. Assuming that the drug AUCs in contralateral eye were equal to the systemic pathway contribution to AUCs in the ipsilateral eye, the percent contribution of local pathways as opposed to systemic circulation for celecoxib delivery to the ipsilateral eye tissues was estimated to be 98% or greater.Conclusions. The retinal delivery of celecoxib was substantially higher following subconjunctival administration compared to the intraperitoneal route. The transscleral pathway almost completely accounts for the retinal celecoxib delivery following subconjunctival administration.