降眼压药物（PGF2α 类似物-比马前列素、拉坦前列素和曲伏前列素）与兔角膜上的 MDR 外排泵的相互作用。
Interaction of ocular hypotensive agents (PGF2 alpha analogs-bimatoprost, latanoprost, and travoprost) with MDR efflux pumps on the rabbit cornea.
机构信息
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64110, USA.
出版信息
J Ocul Pharmacol Ther. 2009 Dec;25(6):487-98. doi: 10.1089/jop.2009.0049.
PURPOSE
The objectives of this work were (i) to screen ocular hypotensive prostaglandin (PGF2 alpha) analogs--bimatoprost, latanoprost, and travoprost as well as their free acid forms--for interaction with efflux pumps on the cornea and (ii) to assess the modulation of efflux upon co-administration of these prostaglandin analogs.
METHODS
Cultured rabbit primary corneal epithelial cells (rPCEC) were employed as an in vitro model for rabbit cornea. Transporter-specific interaction studies were carried out using Madin-Darby canine kidney (MDCK) cells overexpressing MDR1, MRP1, MRP2, MRP5, and BCRP. Freshly excised rabbit cornea was used as an ex vivo model to determine transcorneal permeability.
RESULTS
Cellular accumulation studies clearly showed that all prostaglandin analogs and their free acid forms are substrates of MRP1, MRP2, and MRP5. Bimatoprost was the only prostaglandin analog in this study to interact with P-gp. In addition, none of these molecules showed any affinity for BCRP. K (i) values of these prostaglandin analogs obtained from dose-dependent inhibition of erythromycin efflux in rPCEC showed bimatoprost (82.54 microM) and travoprost (94.77 microM) to have similar but higher affinity to efflux pumps than latanoprost (163.20 microM). Ex vivo studies showed that the permeation of these molecules across cornea was significantly elevated in the presence of specific efflux modulators. Finally, both in vitro and ex vivo experiments demonstrated that the efflux of these prostaglandin analogs could be modulated by co-administering them together.
CONCLUSION
Bimatoprost, latanoprost, travoprost, and their free acid forms are substrates of multiple drug efflux pumps on the cornea. Co-administration of these molecules together is a viable strategy to overcome efflux, which could simultaneously elicit a synergistic pharmacological effect, since these molecules have been shown to activate different receptor population for the reduction of intraocular pressure (IOP).
目的
本研究的目的是（i）筛选眼部降眼压前列腺素（PGF2α）类似物-比马前列素、拉坦前列素和曲伏前列素及其游离酸形式-与角膜上的外排泵相互作用，（ii）评估这些前列腺素类似物共同给药时对外排的调节。
方法
采用培养的兔原代角膜上皮细胞（rPCEC）作为兔角膜的体外模型。采用过表达 MDR1、MRP1、MRP2、MRP5 和 BCRP 的 Madin-Darby 犬肾（MDCK）细胞进行转运体特异性相互作用研究。新鲜兔角膜用作测定角膜通透性的离体模型。
结果
细胞积累研究清楚地表明，所有前列腺素类似物及其游离酸形式均为 MRP1、MRP2 和 MRP5 的底物。本研究中，只有比马前列素是唯一与 P-糖蛋白相互作用的前列腺素类似物。此外，这些分子均与 BCRP 无亲和力。从 rPCEC 中红霉素外排的剂量依赖性抑制获得的这些前列腺素类似物的 K（i）值表明，比马前列素（82.54 μM）和曲伏前列素（94.77 μM）对流出泵的亲和力与拉坦前列素（163.20 μM）相似但更高。离体研究表明，这些分子在存在特定外排调节剂时穿过角膜的通透性显著增加。最后，体内和体外实验均表明，这些前列腺素类似物的外排可以通过共同给药来调节。
结论
比马前列素、拉坦前列素、曲伏前列素及其游离酸形式是角膜上多种药物外排泵的底物。这些分子的共同给药是克服外排的可行策略，因为这些分子已被证明通过激活不同的受体群体来降低眼内压（IOP），从而产生协同的药理作用。
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