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.
Footnotes
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We appreciate the financial support provided by the Australian Institute of Chinese Medicine (Grants R-106-00257 and R-106-00282).
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J.C., X.C., and J.L. contributed equally to this work.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.010801.
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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; MK-571 (L-660,711), 3-[[3-[2-(7-chloroquinolin-2-yl)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; t½β, elimination half-life; ABC, ATP-binding cassette; AUC, area under the plasma concentration-time curve; Cmax, maximum plasma concentration; CL, clearance; Vd, volume of distribution; F, systemic bioavailability; Plumen, permeability calculated based on the disappearance of the drug from the intestinal lumen; Pblood, permeability calculated based on appearance of the drug in the blood; Papp, apparent permeability coefficient; Km, Michaelis-Menten constant; Ki, inhibition constant; RU60079, 2-butyl-4-(methylthio)-1-((2′-(((propylamino)carbonyl)amino)sulfonyl)(1,1′-biphenyl)-4-yl)methyl)-1H-imidazole-5-carboxylic acid sulfone.
- Received April 24, 2006.
- Accepted January 3, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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