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
-
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; 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
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
