Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
Drug Metab Dispos. 2010 Oct;38(10):1790-7. doi: 10.1124/dmd.110.032672. Epub 2010 Jul 1.
The objective of the present study was to investigate the effect of topically coadministered P-glycoprotein (P-gp) substrates/inhibitors on the vitreal kinetics of a systemically administered P-gp substrate. Anesthetized male rabbits were used in these studies. The concentration-time profile of quinidine in the vitreous humor, after intravenous administration, was determined alone and in the presence of topically coadministered verapamil, prednisolone sodium phosphate (PP), and erythromycin. The vitreal pharmacokinetic parameters of quinidine in the presence of verapamil [apparent elimination rate constant (λ(z)), 0.0027 ± 0.0002 min(-1); clearance (CL_F), 131 ± 21 ml/min; area under the curve (AUC(0-∞)), 39 ± 7.0 μg · min/ml; and mean residence time, 435 ± 20 min] were significantly different from those of the control (0.0058 ± 0.0006 min(-1), 296 ± 46 ml/min, 17 ± 3 μg · min/ml, and 232 ± 20 min, respectively). A 1.7-fold decrease in the vitreal λ(z) and a 1.5-fold increase in the vitreal AUC of quinidine were observed in the presence of topical PP. Statistically significant differences between the vitreal profiles of the control and erythromycin-treated group were also observed. Plasma concentration-time profiles of quinidine, alone or in the presence of the topically instilled compounds, remained unchanged, indicating uniform systemic quinidine exposure across groups. This study demonstrates an interaction between topically and systemically coadministered P-gp substrates, probably through the modulation of P-gp on the basolateral membrane of the retinal pigmented epithelium, leading to changes in the vitreal kinetics of the systemically administered agent.
本研究旨在考察局部给予 P-糖蛋白（P-gp）底物/抑制剂对系统给予 P-gp 底物在玻璃体内药动学的影响。这些研究使用麻醉雄性兔。单独和局部联合给予维拉帕米、磷酸泼尼松龙（PP）和红霉素后，测定静脉给予奎尼丁在玻璃体内的浓度-时间曲线。维拉帕米存在时，奎尼丁在玻璃体内的药动学参数[表观消除速率常数（λ（z）），0.0027 ± 0.0002 min（-1）；清除率（CL_F），131 ± 21 ml/min；曲线下面积（AUC（0-∞）），39 ± 7.0 μg · min/ml；和平均驻留时间，435 ± 20 min]与对照（0.0058 ± 0.0006 min（-1），296 ± 46 ml/min，17 ± 3 μg · min/ml，和 232 ± 20 min）相比有显著差异。局部给予 PP 时，玻璃体内 λ（z）降低 1.7 倍，奎尼丁玻璃体内 AUC 增加 1.5 倍。在局部给予红霉素的兔与对照组兔之间也观察到玻璃体内药动学特征的统计学差异。奎尼丁的血浆浓度-时间曲线，无论是单独存在还是与局部给予的化合物一起存在，都保持不变，表明各组之间系统给予的奎尼丁暴露均匀。这项研究表明，局部和系统联合给予 P-gp 底物之间存在相互作用，可能是通过视网膜色素上皮基底外侧膜上的 P-gp 调节，导致系统给予的药物在玻璃体内的药动学发生变化。
