Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra.
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 IC(50) value of 2.56 microM, but stimulated PgP/MDR1 ATPase activity with a K(m) of 25.1 microM. 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.
Cao
Jie
J
Department of Pharmacy, School of Life Sciences, Queensland University of Technology, 2 George Street, Brisbane, Queensland 4001 Australia.
Chen
Xiao
X
Liang
Jun
J
Yu
Xue-Qing
XQ
Xu
An-Long
AL
Chan
Eli
E
Wei
Duan
D
Huang
Min
M
Wen
Jing-Yuan
JY
Yu
Xi-Yong
XY
Li
Xiao-Tian
XT
Sheu
Fwu-Shan
FS
Zhou
Shu-Feng
SF
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D004077:Digoxin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics*; D005419:Flavonoids / Q000008:administration & dosage / Q000097:blood / Q000302:isolation & purification / Q000493:pharmacokinetics*; D020719:Glucuronides / Q000378:metabolism; D006035:Glycyrrhiza / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007529:Isoflavones; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D010636:Phenols / Q000008:administration & dosage / Q000097:blood / Q000302:isolation & purification / Q000493:pharmacokinetics*; D018517:Plant Roots; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014162:Transfection; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D020719:Glucuronides; D007529:Isoflavones; D010636:Phenols; D014535:Uridine Diphosphate Glucuronic Acid; D004077:Digoxin; C095122:multidrug resistance protein 3; D014700:Verapamil; C107601:glabridin