Absorption and metabolism of flavonoids in the Caco-2 cell culture model and a perfused rat intestinal model

被引:216
作者
Liu, Y [1 ]
Hu, M [1 ]
机构
[1] Washington State Univ, Coll Pharm, Dept Pharmaceut Sci, Pullman, WA 99164 USA
关键词
D O I
10.1124/dmd.30.4.370
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The purpose of present study was to determine the intestinal absorption and metabolism of genistein and its analogs to better understand the mechanisms responsible for their low oral bioavailability. The Caco-2 cell culture model and a perfused rat intestinal model were used for the study. In both models, permeabilities of aglycones (e.g., genistein) were comparable to well absorbed compounds, such as testosterone and propranolol. In the Caco-2 model, permeabilities of aglycones were at least 5 times higher (p < 0.05) than their corresponding glycosides (e.g., genistin), and the vectorial transport of aglycones was similar (p > 0.05). In contrast, vectorial transport of glucosides favored excretion (p < 0.05). Limited hydrolysis of glycosides was observed in the Caco-2 model, which was completely inhibited (p < 0.05) by 20 mM gluconolactone, a broad specificity glycosidase inhibitor. In the perfused rat intestinal model, genistin was rapidly hydrolyzed (about 40% in 15 min) in the upper intestine but was not hydrolyzed at all in the colon. Aglycones were rapidly absorbed (P*(eff) > 1.5), and absorbed aglycones underwent extensive (40% maximum) phase II metabolism via glucuronidation and sulfation in the upper small intestine. Similar to the hydrolysis, recovery of conjugated genistein was also region-dependent, with jejunum having the highest and colon the lowest (p < 0.05). This difference in conjugate recovery could be due to the difference in the activities of enzymes or efflux transporters, and the results of studies tend to suggest that both of these factors were involved. In conclusion, genistein and its analogs are well absorbed in both intestinal models, and therefore, poor absorption is not the reason for its low bioavailability. On the other hand, extensive phase II metabolism in the intestine significantly contributes to its low bioavailability.
引用
收藏
页码:370 / 377
页数:8
相关论文
共 35 条
[1]   ESTIMATING HUMAN ORAL FRACTION DOSE ABSORBED - A CORRELATION USING RAT INTESTINAL-MEMBRANE PERMEABILITY FOR PASSIVE AND CARRIER-MEDIATED COMPOUNDS [J].
AMIDON, GL ;
SINKO, PJ ;
FLEISHER, D .
PHARMACEUTICAL RESEARCH, 1988, 5 (10) :651-654
[2]   Isoflavones from Tofu are absorbed and metabolized in the isolated rat small intestine [J].
Andlauer, W ;
Kolb, J ;
Fürst, P .
JOURNAL OF NUTRITION, 2000, 130 (12) :3021-3027
[3]   CORRELATION BETWEEN ORAL-DRUG ABSORPTION IN HUMANS AND APPARENT DRUG PERMEABILITY COEFFICIENTS IN HUMAN INTESTINAL EPITHELIAL (CACO-2) CELLS [J].
ARTURSSON, P ;
KARLSSON, J .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1991, 175 (03) :880-885
[4]   Role of transport proteins in drug absorption, distribution and excretion [J].
Ayrton, A ;
Morgan, P .
XENOBIOTICA, 2001, 31 (8-9) :469-497
[5]   THE INFLUENCE OF PEPTIDE STRUCTURE ON TRANSPORT ACROSS CACO-2 CELLS [J].
CONRADI, RA ;
HILGERS, AR ;
HO, NFH ;
BURTON, PS .
PHARMACEUTICAL RESEARCH, 1991, 8 (12) :1453-1460
[6]   Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen [J].
Crespy, V ;
Morand, C ;
Manach, C ;
Besson, C ;
Demigne, C ;
Remesy, C .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 1999, 277 (01) :G120-G126
[7]  
Czernik PJ, 2000, DRUG METAB DISPOS, V28, P1210
[8]   Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase [J].
Day, AJ ;
Cañada, FJ ;
Díaz, JC ;
Kroon, PA ;
Mclauchlan, R ;
Faulds, CB ;
Plumb, GW ;
Morgan, MRA ;
Williamson, G .
FEBS LETTERS, 2000, 468 (2-3) :166-170
[9]   Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver β-glucosidase activity [J].
Day, AJ ;
DuPont, MS ;
Ridley, S ;
Rhodes, M ;
Rhodes, MJC ;
Morgan, MRA ;
Williamson, G .
FEBS LETTERS, 1998, 436 (01) :71-75
[10]  
Fischer E, 1996, Acta Physiol Hung, V84, P287