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Drug Metabolism and Disposition Fast Forward
First published on January 12, 2007; DOI: 10.1124/dmd.106.010801

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Received for publication April 25, 2006.
Revised November 8, 2006.
Accepted for publication January 3, 2007.

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

Jie Cao 1, Xiao Chen 2, Jun Liang 3, Xue-Qing Yu 4, An-Long Xu 5, Eli Chan 6, Wei Duan 7, Min Huang 8, Jing-Yuan Wen 9, Xi-Yong Yu 10, Xiao-Tian Li 11, Fwu-Shan Sheu 12, Shu-Feng Zhou 13*

1 Department of General Surgery, the First Municipal Hospital of Guangzhou, Guangzhou, China 2 Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China 3 Department of Pharmacology and Toxicology, Australian Institute of Traditional Chinese Medicine, Syd 4 Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China 5 Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou, China 6 Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 7 Institute of Biotechnology, Deakin University, Waurn Ponds, Victoria 3217, Australia 8 Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guang 9 School of Pharmacy, Faculty of Medical and Health Sciences, the University of Auckland, Auckland, Ne 10 Department of Molecular & Clinical Pharmacology, Guangdong Provincial Cardiovascular Institute. 96 D 11 Department of Maternal Medicine, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, Chi 12 Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 13 Australian Institute of Traditional Chinese Medicine

* Address correspondence to: E-mail: shufengzhou2006{at}hotmail.com

Abstract

Glabridin is a major constituent of the root of Glycyrrhiza glabra, which is commonly used in 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 about 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 about 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 that 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 wildtype mice. These findings indicate that glabridin is a substrate for PgP and both PgP/MDR1-mediated efflux and first-pass metabolism contribute to the low oral bioavailability of glabridin.


Key words: ABC transporters, absorption, bioavailability, drug disposition, intestinal transport, mass spectrometry, membrane permeability, p-glycoprotein, pharmacokinetics




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