CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal.
Food Chem Toxicol. 2018 Jan;111:84-93. doi: 10.1016/j.fct.2017.11.004. Epub 2017 Nov 6.
The combined use of different P-glycoprotein (P-gp) inhibitors may be a relevant approach to the synergistic and safer inhibition of the P-gp-mediated drug efflux. Herein, we aimed to explore dual combinations of the flavonoids baicalein, (-)-epigallocatechin gallate, kaempferol, quercetin and silymarin to reverse the interference of P-gp on the intracellular accumulation of antiepileptic drugs (AEDs). The intracellular accumulation of rhodamine 123 (a classic P-gp substrate) and of several commonly used AEDs (carbamazepine, phenytoin, oxcarbazepine) or their metabolites (carbamazepine-10,11-epoxide and licarbazepine) was evaluated in MDCK-MDR1 cells in the presence and absence of individual flavonoids and their combinations. A selected flavonoid combination [(-)-epigallocatechin gallate/silymarin] was also evaluated in transepithelial transport experiments using licarbazepine (active metabolite of oxcarbazepine) as a model compound. Most flavonoid combinations increased rhodamine 123 intracellular uptake in a greater extent than their additive individual effects at similar concentrations. Moreover, selected (-)-epigallocatechin gallate/silymarin and kaempferol/baicalein combinations also enhanced the intracellular accumulation of all AEDs and metabolites. Overall, the combination of (-)-epigallocatechin gallate/silymarin was the most promising one. Thus, dual flavonoid combinations may be useful to overcome the P-gp-mediated efflux of AEDs and their metabolites, making their association to AED therapy a potentially valuable approach to circumvent pharmacoresistance in epilepsy.
联合使用不同的 P 糖蛋白（P-gp）抑制剂可能是一种相关的方法，可以协同且更安全地抑制 P-gp 介导的药物外排。在此，我们旨在探索黄酮类化合物黄芩素、（-）-表没食子儿茶素没食子酸酯、山奈酚、槲皮素和水飞蓟素的双重组合，以逆转 P-gp 对几种抗癫痫药物（AEDs）的细胞内积累的干扰。在 MDCK-MDR1 细胞中，评估了单独黄酮类化合物及其组合存在和不存在的情况下，罗丹明 123（一种经典的 P-gp 底物）和几种常用的 AEDs（卡马西平、苯妥英、奥卡西平）或其代谢物（卡马西平-10、11-环氧化物和利卡巴嗪）的细胞内积累。还使用利卡巴嗪（奥卡西平的活性代谢物）作为模型化合物，在跨上皮转运实验中评估了选定的黄酮类化合物组合[（-）-表没食子儿茶素没食子酸酯/水飞蓟素]。大多数黄酮类化合物组合在相似浓度下以比其单独作用更大的程度增加了罗丹明 123 的细胞内摄取。此外，选定的（-）-表没食子儿茶素没食子酸酯/水飞蓟素和山奈酚/黄芩素组合也增强了所有 AEDs 和代谢物的细胞内积累。总体而言，（-）-表没食子儿茶素没食子酸酯/水飞蓟素的组合最有前景。因此，双重黄酮类化合物组合可能有助于克服 AED 及其代谢物的 P-gp 介导的外排，使它们与 AED 治疗的联合成为规避癫痫药物耐药性的一种潜在有价值的方法。
