Increased Plasma Exposures of Five Protoberberine Alkaloids from Coptidis Rhizoma in Streptozotocin-Induced Diabetic Rats: Is P-GP Involved?
Increased Plasma Exposures of Five Protoberberine Alkaloids from Coptidis Rhizoma in Streptozotocin-Induced Diabetic Rats: Is P-GP Involved?
复制标题
在链脲佐菌素诱导的糖尿病大鼠中，黄连五种原小檗碱生物碱的血浆暴露量增加：是否涉及 P-GP？
DOI：
10.1055/s-0029-1240815
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发表时间：
2010-06-01
期刊：
影响因子：
2.7
通讯作者：
Wang, Guangji
中科院分区：
文献类型：
--
作者：
Yu, Sen;Yu, Yunli;Wang, Guangji
我们先前的研究表明，在6周的链脲佐菌素（STZ）诱导的糖尿病大鼠口服黄芪提取物后，小檗碱，巴马汀，黄连碱，表小檗碱和药根碱的暴露量较高。本研究旨在探讨STZ诱导的糖尿病大鼠肠道P-糖蛋白（P-GP）的功能和表达是否下调，以及P-GP功能和表达的受损是否与5种原小檗碱生物碱的暴露量增加有关。采用门静脉给药法，测定大鼠口服黄芪提取物后门静脉血药浓度-时间曲线。采用在体小肠单向灌流法测定药物在十二指肠和回肠的有效渗透性。通过测定罗丹明123（Rho 123）的吸收来评估大鼠肠道中P-GP的功能。使用蛋白质印迹法评价P-GP水平。结果表明，糖尿病大鼠门静脉中5种生物碱的C（max）和AUC（0-8）值均显著高于对照组。糖尿病大鼠门静脉Rho 123水平升高，提示P-GP功能受损。在糖尿病大鼠的十二指肠中使用原位单向肠灌注发现测试药物的更高有效渗透性，表明小檗碱和Rho 123更容易穿过糖尿病大鼠的肠屏障转运。糖尿病大鼠十二指肠、空肠和回肠中P-GP蛋白水平较同龄对照组明显降低。上述结果提示，STZ诱导的糖尿病大鼠肠道P-GP功能和表达受损，这可能与5种原小檗碱类生物碱暴露量增加有关。
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.