Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, P R China.
Planta Med. 2010 Jun;76(9):876-81. doi: 10.1055/s-0029-1240815. Epub 2010 Jan 27.
Our previous study showed a higher exposure of berberine, palmatine, coptisine, epiberberine and jatrorrhizine in 6-week streptozotocin (STZ)-induced diabetic rats, after oral administration of Coptidis Rhizoma extract. The aim of the present study was to investigate whether the function and expression of intestinal P-glycoprotein (P-GP) was downregulated in STZ-induced diabetic rats and if the impairment of P-GP function and expression contributed to the exposure increase of the five protoberberine alkaloids. Plasma concentration-time profiles of the drugs in the portal vein were obtained after oral administration of Coptidis Rhizoma extract. The effective permeability of the drug across duodenum and ileum were measured using in situ single-pass intestine perfusion. P-GP function in the rat intestine was assessed by measuring the absorption of rhodamine 123 (Rho123). P-GP levels were evaluated using Western blots. It was found that the C(max) and AUC(0-8) values of five alkaloids in the portal vein of diabetic rats were significantly higher than those in the control rats. Diabetic rats also exhibitd a higher level of Rho123 in the portal vein, which showed impairment of P-GP function. A higher effective permeability of the tested drug was found in the duodenum of diabetic rats using in situ single-pass intestine perfusion, indicating that berberine and Rho123 transported more easily across the intestinal barrier of diabetic rats. A lower level of P-GP protein was found in the duodenum, jejunum and ileum of the diabetic rats as compared with age-matched control rats. All these results suggested that the function and expression of P-GP were impaired in the intestine of STZ-induced diabetic rats which, at least partly, contributed to the exposure increase of the five protoberberine alkaloids.
我们之前的研究表明，在给予黄连提取物后，6 周链脲佐菌素（STZ）诱导的糖尿病大鼠中，小檗碱、巴马汀、黄连碱、表小檗碱和药根碱的暴露量更高。本研究旨在探讨 STZ 诱导的糖尿病大鼠的肠道 P-糖蛋白（P-GP）功能和表达是否下调，以及 P-GP 功能和表达的损害是否导致这五种原小檗碱类生物碱的暴露量增加。通过口服黄连提取物后，在门静脉中获得药物的血浆浓度-时间曲线。使用原位单次肠灌注法测量药物在十二指肠和回肠中的有效渗透系数。通过测量 rhodamine 123（Rho123）的吸收来评估大鼠肠道中的 P-GP 功能。使用 Western blot 评估 P-GP 水平。结果发现，糖尿病大鼠门静脉中五种生物碱的 Cmax 和 AUC（0-8）值明显高于对照组大鼠。糖尿病大鼠门静脉中 Rho123 水平也较高，表明 P-GP 功能受损。原位单次肠灌注显示，糖尿病大鼠十二指肠中测试药物的有效渗透系数更高，表明小檗碱和 Rho123 更容易穿过糖尿病大鼠的肠屏障。与年龄匹配的对照组大鼠相比，糖尿病大鼠的十二指肠、空肠和回肠中 P-GP 蛋白水平较低。所有这些结果表明，STZ 诱导的糖尿病大鼠肠道中的 P-GP 功能和表达受损，这至少部分导致了这五种原小檗碱类生物碱的暴露量增加。
