Ravikumar Reddy D, Khurana Amit, Bale Swarna, Ravirala Ramu, Samba Siva Reddy V, Mohankumar M, Godugu Chandraiah
Laboratory of Nano-Biology, Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana State 500037 India.
Department of Drug Metabolism and Pharmacokinetics, Syngene International Ltd, Bangalore, Karnataka India.
Springerplus. 2016 Sep 20;5(1):1618. doi: 10.1186/s40064-016-3267-1. eCollection 2016.
P-glycoprotein (P-gp), a well known efflux transporter in the blood brain barrier inhibits the uptake of substrate drugs into brain. The main aim of this study is to evaluate the effect of natural product based P-gp inhibitors on brain penetration of various CNS drugs which are P-gp substrates. In this study, we have evaluated the inhibitory effects of natural bioflavonoids (quercetin and silymarin) on P-gp by using digoxin and quinidine as model P-gp model substrate drugs. In vitro inhibitory effects were evaluated in Caco-2 cell lines using digoxin as a model drug and in vivo P-gp inhibiting effect was evaluated in mice model using quinidine as model drug. The accumulation and bidirectional transport of digoxin in Caco-2 cells was determined in presence and absence of quercetin and silymarin. Elacridar was used as standard P-gp inhibitor and used to compare the inhibitory effects of test compounds. The apical to basolateral transport of digoxin was increased where as basolateral to apical transport of digoxin was decreased in concentration dependent manner in the presence of elacridar, quercetin and silymarin. After intravenous administration of P-gp inhibitors, brain levels of quinidine were estimated using LC-MS method. Increased brain uptake was observed with quercetin (2.5-fold) and silymarin (3.5-fold). Though the brain penetration potential of P-gp substrates was lower than that observed in elacridar, both quercetin and silymarin improved plasma quinidine levels. Caco-2 permeability studies and brain uptake indicate that both quercetin and silymarin can inhibit P-gp mediated efflux of drug into brain. Our results suggest that both silymarin and quercetin could potentially increase the brain distribution of co-administered drugs that are P-gp substrates.
P-糖蛋白（P-gp）是血脑屏障中一种著名的外排转运蛋白，可抑制底物药物进入大脑。本研究的主要目的是评估基于天然产物的P-gp抑制剂对多种作为P-gp底物的中枢神经系统药物脑渗透的影响。在本研究中，我们以地高辛和奎尼丁作为P-gp模型底物药物，评估了天然生物黄酮类化合物（槲皮素和水飞蓟宾）对P-gp的抑制作用。使用地高辛作为模型药物在Caco-2细胞系中评估体外抑制作用，使用奎尼丁作为模型药物在小鼠模型中评估体内P-gp抑制作用。在存在和不存在槲皮素和水飞蓟宾的情况下，测定地高辛在Caco-2细胞中的积累和双向转运。依拉曲沙用作标准P-gp抑制剂，用于比较受试化合物的抑制作用。在依拉曲沙、槲皮素和水飞蓟宾存在的情况下，地高辛从顶端到基底外侧的转运增加，而从基底外侧到顶端的转运以浓度依赖的方式降低。静脉注射P-gp抑制剂后，使用液相色谱-质谱法估计奎尼丁的脑内水平。观察到槲皮素（2.5倍）和水飞蓟宾（3.5倍）使脑摄取增加。尽管P-gp底物的脑渗透潜力低于依拉曲沙，但槲皮素和水飞蓟宾均提高了血浆奎尼丁水平。Caco-2通透性研究和脑摄取表明，槲皮素和水飞蓟宾均可抑制P-gp介导的药物向脑内的外排。我们的结果表明水飞蓟宾和槲皮素均可能增加共同给药的作为P-gp底物的药物在脑内的分布。
