Poor oral bioavailability of a promising anticancer agent andrographolide is due to extensive metabolism and efflux by P‐glycoprotein

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 as14‐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 (Papp) of AP from basolateral (B) to apical (A) (4.94 × 10 cm/s) in the Caco‐2 model was four times higher than the Papp 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. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:5007-5017, 2011