PT - JOURNAL ARTICLE AU - Jie Cao AU - Xiao Chen AU - Jun Liang AU - Xue-Qing Yu AU - An-Long Xu AU - Eli Chan AU - Duan Wei AU - Min Huang AU - Jing-Yuan Wen AU - Xi-Yong Yu AU - Xiao-Tian Li AU - Fwu-Shan Sheu AU - Shu-Feng Zhou TI - Role of P-glycoprotein in the Intestinal Absorption of Glabridin, an Active Flavonoid from the Root of <em>Glycyrrhiza glabra</em> AID - 10.1124/dmd.106.010801 DP - 2007 Apr 01 TA - Drug Metabolism and Disposition PG - 539--553 VI - 35 IP - 4 4099 - http://dmd.aspetjournals.org/content/35/4/539.short 4100 - http://dmd.aspetjournals.org/content/35/4/539.full SO - Drug Metab Dispos2007 Apr 01; 35 AB - Glabridin is a major constituent of the root of Glycyrrhiza glabra, which is commonly used in the treatment of cardiovascular and central nervous system diseases. This study aimed to investigate the role of P-glycoprotein (PgP/MDR1) in the intestinal absorption of glabridin. The systemic bioavailability of glabridin was approximately 7.5% in rats, but increased when combined with verapamil. In single-pass perfused rat ileum with mesenteric vein cannulation, the permeability coefficient of glabridin based on drug disappearance in luminal perfusates (Plumen) was approximately 7-fold higher than that based on drug appearance in the blood (Pblood). Glabridin was mainly metabolized by glucuronidation, and the metabolic capacity of intestine microsomes was 1/15 to 1/20 of that in liver microsomes. Polarized transport of glabridin was found in Caco-2 and MDCKII monolayers. Addition of verapamil in both apical (AP) and basolateral (BL) sides abolished the polarized transport of glabridin across Caco-2 cells. Incubation of verapamil significantly altered the intracellular accumulation and efflux of glabridin in Caco-2 cells. The transport of glabridin in the BL-AP direction was significantly higher in MDCKII cells overexpressing PgP/MDR1 than in the control cells. Glabridin inhibited PgP-mediated transport of digoxin with an IC50 value of 2.56 μM, but stimulated PgP/MDR1 ATPase activity with a Km of 25.1 μM. The plasma AUC0–24h of glabridin in mdr1a(–/–) mice was 3.8-fold higher than that in wild-type mice. These findings indicate that glabridin is a substrate for PgP and that both PgP/MDR1-mediated efflux and first-pass metabolism contribute to the low oral bioavailability of glabridin. The American Society for Pharmacology and Experimental Therapeutics