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

Abstract

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 (P lumen ) was approximately 7-fold higher than that based on drug appearance in the blood (P blood ). There is an increasing consumption of herbal medicines in recent years in Asian and Western countries. Their incorporation into the medical care system has been encouraged by the World Health Organization despite the lack of evidence for the efficacy of most herbal drugs. Herbal medicines are usually orally administered with longterm regimens. However, the nature of intestinal absorption of the major ingredients of most herbal medicines is unknown, probably because of a lack of sensitive analytical methods, difficulties in the choice of marker components, and difficulties in the establishment and validation of efficient study models. The widely used traditional Chinese medicine, the root of Glycyrrhiza glabra (licorice), is one of the most commonly used herbal medicines in the world because of its exceptional pharmacological properties recognized by traditional Chinese medicine (Zhu, 1998). Licorice has been used as antidotes,We appreciate the financial support provided by the Australian Institute of Chinese Medicine (Grants R-106-00257 and R-106-00282).J.C., X.C., and J.L. contributed equally to this work. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.106.010801. ABBREVIATIONS:PgP, P-glycoprotein; MDR, multidrug resistance; MRP, multidrug resistance-associated protein; MDCK, Madin-Darby canine kidney; HPLC, high performance liquid chromatography; HBSS, Hanks' balanced salt solution; DMSO, dimethyl sulfoxide; UDPGA, uridine diphosphate glucuronic acid; 711),vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid; LC-MS, liquid chromatography-mass spectrometry; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide; PBS, phosphate-buffered saline; IS, internal standard; TEER, transepithelial electric resistance; AP, apical; BL, basolateral; t 1/2␤ , elimination half-life; ABC, ATP-binding cassette; AUC, area under the plasma concentration-time curve; C max , maximum plasma concentration; CL, clearance; V d , volume of distribution; F, systemic bioavailability; P lumen , permeability calculated based on the disappearance of the drug from the intestinal lumen; P blood , permeability calculated based on appearance of the drug in the blood; P app , apparent permeability coefficient; K m , Michaelis-Menten

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