Coptidis Rhizoma (CR), the rhizome of Coptis chinensis FRANCH, is a popular Chinese herb. CR contains plenty of isoquinoline alkaloids such as berberine, coptisine and palmatine. Cyclosporine (CSP), an important immunosuppressant with narrow therapeutic window, is employed as a probe substrate of P-glycoprotein (P-gp) and CYP3A4 in order to investigate the in vivo modulation effect of CR on P-gp and CYP3A4. Three groups of rats were orally administered CSP without and with single dose or repeated dosing of CR in a parallel design. Blood samples were collected at specific time points and the blood CSP concentration was determined by a specific monoclonal fluorescence polarization immunoassay. The results showed that a single dose (1.0 g/kg) and the 7th dose (1.0 g/kg) of CR significantly decreased the Cmax of CSP by 56.9% and 70.4%, and reduced the AUC0-540 by 56.4% and 68.7%, respectively. Cell study indicated that CR decoction, berberine, coptisine, palmatine all activated the efflux transport of P-gp. Ex-vivo study showed that the serum metabolites of CR activated CYP 3A4. In conclusion, through using CSP as an in vivo probe substrate, we have verified that oral intake of CR activated the functions of P-gp and CYP3A based on in vivo and in vitro studies.

中文翻译：

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黄连在体内对 P-糖蛋白和 CYP 3A 的激活 : 以环孢菌素作为大鼠的探针底物

黄连（Coptidis Rhizoma，CR）是黄连的根茎，是一种流行的中草药。CR含有大量的异喹啉类生物碱，如黄连素、黄连碱和巴马汀。环孢素（CSP）是一种治疗窗窄的重要免疫抑制剂，被用作P-糖蛋白（P-gp）和CYP3A4的探针底物，以研究CR对P-gp和CYP3A4的体内调节作用。在平行设计中，三组大鼠口服 CSP，没有和单剂量或重复给药 CR。在特定时间点采集血样，并通过特异性单克隆荧光偏振免疫测定法测定血液 CSP 浓度。结果表明，单剂量（1.0 g/kg）和第7剂（1.0 g/kg）CR显着降低CSP的Cmax 56.9%和70.4%，并将 AUC0-540 分别降低 56.4% 和 68.7%。细胞研究表明，CR煎剂、黄连素、黄连碱、巴马汀均能激活P-gp的外排转运。体外研究表明，CR 的血清代谢物可激活 CYP 3A4。总之，通过使用CSP作为体内探针底物，我们已经基于体内和体外研究验证了口服CR可激活P-gp和CYP3A的功能。