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Title: Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra
Authors: Cao, J.
Chen, X.
Liang, J.
Yu, X.-Q.
Xu, A.-L.
Chan, E. 
Duan, W.
Huang, M.
Wen, J.-Y.
Yu, X.-Y.
Li, X.-T.
Sheu, F.-S. 
Zhou, S.-F.
Issue Date: Apr-2007
Citation: Cao, J., Chen, X., Liang, J., Yu, X.-Q., Xu, A.-L., Chan, E., Duan, W., Huang, M., Wen, J.-Y., Yu, X.-Y., Li, X.-T., Sheu, F.-S., Zhou, S.-F. (2007-04). Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra. Drug Metabolism and Disposition 35 (4) : 539-553. ScholarBank@NUS Repository.
Abstract: 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. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics.
Source Title: Drug Metabolism and Disposition
ISSN: 00909556
DOI: 10.1124/dmd.106.010801
Appears in Collections:Staff Publications

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