穿心莲内酯
生物利用度
P-糖蛋白
空肠
药理学
回肠
维拉帕米
首过效应
化学
流出
药代动力学
葡萄糖醛酸化
穿心莲
十二指肠
肠道通透性
碳酸钙-2
小肠
医学
生物化学
体外
内科学
多重耐药
病理
钙
抗生素
替代医学
有机化学
微粒体
作者
Ling Ye,Tao Wang,Lan Tang,Wei Liu,Zhen Yang,Juan Zhou,Zhijie Zheng,Zheng Cai,Ming Hu,Zhongqiu Liu
摘要
Andrographolide (AP), isolated from Andrographis paniculata (Burm. F.) Nees, is an anticancer agent with significant clinical potential. This study determined its oral bioavailability and how intestinal disposition affects its bioavailability. Pharmacokinetics was evaluated in rats. Intestinal disposition was determined using a single-pass rat intestinal perfusion model and the cultured Caco-2 cells and Madin-Darby canine kidney II cells over expressing human P-gp (MDR1-MDCKII). Absolute bioavailability of AP was 2.67%. In the duodenum and jejunum, AP was rapidly metabolized to a sulfonate, identified as 14-deoxy-12-sulfo- andrographolide. AP was also rapidly metabolized by liver S9 fraction and in blank perfusates collected from duodenum and jejunum. The apparent permeability (P(app) ) of AP from basolateral (B) to apical (A) (4.94 × 10 cm/s) in the Caco-2 model was four times higher than the P(app) from A to B (1.14 × 10(-5) cm/s). Moreover, AP was significantly more permeable in the B to A direction than the opposite direction in MDR1-MDCKII cells. In the perfusion model, the effective permeability (P*(eff) ) for AP was highest in the duodenum, followed by jejunum, and then ileum and colon. In the ileum and colon, the P*(eff) for AP was significantly increased by verapamil, a P-glycoprotein (P-gp) inhibitor. AP has poor oral bioavailability because of its rapid biotransformation and efflux by P-gp.
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