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Role of P-glycoprotein in the Intestinal Absorption of Glabridin, an Active Flavonoid from the Root of Glycyrrhiza glabra

Department of General Surgery, the First Municipal Hospital of Guangzhou, Guangzhou, China (J.C.); Departments of Pharmacy (X.C.) and Nephrology (X.-Q.Y.), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Pharmacology and Toxicology, Australian Institute of Chinese Medicine, Sydney, New South Wales, Australia (J.L., S.-F.Z.); Department of Biochemistry, School of Life Sciences (A.-L.X.), and Institute of Clinical Pharmacology, School of Pharmaceutical Sciences (M.H.), Sun Yat-sen University, Guangzhou, China; Departments of Pharmacy (E.C.) and Biological Sciences (F.-S.S.), Faculty of Science, National University of Singapore, Singapore; School of Pharmacy, Faculty of Medical and Health Sciences, the University of Auckland, Auckland, New Zealand (J.-Y.W.); School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia (W.D.); Department of Molecular & Clinical Pharmacology, Guangdong Provincial Cardiovascular Institute, Guangzhou, China (X.-Y.Y.); and Department of Maternal Medicine, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China (X.-T.L.)

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 (P_lumen) was approximately 7-fold higher than that based on drug appearance in the blood (P_blood). 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 K_m of 25.1 µM. The plasma AUC_0–24h 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.