Dash Ranjeet Prasad, Ellendula Bhanuchander, Agarwal Milee, Nivsarkar Manish
Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research - Ahmedabad, C/O-B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India.
Eur J Pharmacol. 2015 Nov 15;767:67-76. doi: 10.1016/j.ejphar.2015.10.009. Epub 2015 Oct 10.
The aim of this study was to evaluate the change in the expression and the activity of intestinal P-glycoprotein (efflux transporter) with progression of diabetes in rats. Diabetes was induced in Wistar rats using a combination of low dose streptozotocin along with high fat diet. The expression of intestinal P-glycoprotein significantly increased (P≤0.05) with the progression of diabetes which was inferred from the mRNA analysis of mdr1a and mdr1b genes in the ileum segment of rat intestine. Furthermore, a significant increase (P≤0.05) in Na(+)-K(+) ATPase activity was observed in the ileum segment of rat intestine with the progression of diabetes. As a result of this, a significant decrease in the intestinal uptake and peroral bioavailability of the P-glycoprotein substrates (verapamil and atorvastatin) was observed along with the progression of diabetes as compared to normal animals. To address this problem of impaired drug uptake and bioavailability, a reported P-glycoprotein inhibitor, epigallocatechin-3-gallate, was experimentally evaluated. The treatment with epigallocatechin-3-gallate resulted in significant reduction in the expression and activity of P-glycoprotein and subsequent improvement in the intestinal uptake and peroral bioavailability of both verapamil and atorvastatin in normal as well as in diabetic animals. The findings of this study rationalised the use and established the mechanism of action of epigallocatechin-3-gallate to overcome P-glycoprotein mediated drug efflux and will also be helpful in therapeutic drug monitoring in diabetes.
本研究的目的是评估大鼠糖尿病进展过程中肠道P-糖蛋白（外排转运体）表达和活性的变化。采用低剂量链脲佐菌素联合高脂饮食诱导Wistar大鼠患糖尿病。从大鼠肠道回肠段mdr1a和mdr1b基因的mRNA分析推断，随着糖尿病的进展，肠道P-糖蛋白的表达显著增加（P≤0.05）。此外，随着糖尿病的进展，在大鼠肠道回肠段观察到Na(+)-K(+) ATP酶活性显著增加（P≤0.05）。因此，与正常动物相比，随着糖尿病的进展，观察到P-糖蛋白底物（维拉帕米和阿托伐他汀）的肠道摄取和口服生物利用度显著降低。为了解决药物摄取和生物利用度受损的问题，对一种已报道的P-糖蛋白抑制剂表没食子儿茶素-3-没食子酸酯进行了实验评估。用表没食子儿茶素-3-没食子酸酯治疗导致正常动物和糖尿病动物中P-糖蛋白的表达和活性显著降低，随后维拉帕米和阿托伐他汀的肠道摄取和口服生物利用度得到改善。本研究结果为表没食子儿茶素-3-没食子酸酯的使用提供了理论依据，并确立了其克服P-糖蛋白介导的药物外排的作用机制，也将有助于糖尿病的治疗药物监测。
