Modulation of the activity of ABC transporters (P-glycoprotein, MRP2, BCRP) by flavonoids and drug response

Journal of Pharmaceutical Sciences

Volumn 99, Issue 2, 2010, Pages 598-617

  Alvarez, Ana I ^a   Real, Rebeca ^a   Pérez, Miriam ^a   Mendoza, Gracia ^a   Prieto, Julio G ^a   Merino, Gracia ^a  

^a UNIVERSITY OF LEÓN   (Spain)

Author keywords

ABC transporters; BCRP ABCG2; Drug interaction; Flavonoids; MRP2 ABCC2; P glycoprotein ABCB1

Indexed keywords

ABC TRANSPORTER; ALPHA NAPHTHOFLAVONE; AURANTIIN; BIOCHANIN A; BREAST CANCER RESISTANCE PROTEIN; CHRYSIN; CYTOCHROME P450; DIGOXIN; DILTIAZEM; ETOPOSIDE; FLAVONOID; FLAVOPIRIDOL; GENISTEIN; GLYCOPROTEIN P; KAEMPFEROL; MORIN; MOXIDECTIN; MULTIDRUG RESISTANCE PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 2; NARINGENIN; NITROFURANTOIN; NOBILETIN; PACLITAXEL; QUERCETIN; TALINOLOL; TANGERETIN; TOPOTECAN; VERAPAMIL; VINBLASTINE;

DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG HALF LIFE; DRUG INTOXICATION; DRUG RESPONSE; DRUG STRUCTURE; ENZYME INHIBITION; FOOD INTAKE; HUMAN; HYDROLYSIS; INTESTINE ABSORPTION; MOLECULAR INTERACTION; NONHUMAN; PROTEIN EXPRESSION; REVIEW;

EID: 74049143120     PISSN: 00223549     EISSN: 15206017     Source Type: Journal    
DOI: 10.1002/jps.21851     Document Type: Review

References (162)

1. Zhang S, Yang X, Morris ME. 2004. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol Pharmacol 65: 1208-1216.
2. Morris ME, Zhang S. 2006. Flavonoid-drug interactions: Effects of flavonoids on ABC transporters. Life Sci 7:2116-2130.
3. Neuhouser ML. 2004. Dietary flavonoids and cancer risk: Evidence from human population studies. Nutr Cancer 50:1-7.
4. Arts IC, Hollman PC. 2005. Polyphenols and disease risk in epidemiologic studies. Am J Clin Nutr 81:317S-325S.
5. Yao LH, Jiang YM, Shi J, Tomás-Barberán FA, Datta N, Singanusong R, Chen SS. 2004. Flavonoids in food and their health benefits. Plant Foods Hum Nutr 59:113-122.
6. Watanabe S, Uesugi S, Kikuchi Y. 2002. Isoflavones for prevention of cancer, cardiovascular diseases, gynecological problems and possible immune potentiation. Biomed Pharmacother 56: 302-312.
7. Heim KE, Tagliaferro AR, Bobilya DJ. 2002. Flavonoid antioxidants: Chemistry, metabolism and structure-activity relationships. J Nutr Biochem 13:572-584.
8. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. 2004. Polyphenols: Food sources and bioavailability. Am J Clin Nutr 79:727-747.
9. Piskula MK, Terao J. 1998. Accumulation of (-)-epicatechin metabolites in rat plasma after oral administration and distribution of conjugation enzymes in rat tissues. J Nutr 128:1172-1178.
10. Spencer JP, Chowrimootoo G, Choudhury R, Debnam ES, Srai SK, Rice-Evans C. 1999. The small intestine can both absorb and glucuronidate luminal flavonoids. FEBS Lett 458:224-230.
11. Crespy V, Morand C, Besson C, Manach C, Démigné C, Rémésy C. 2001. Comparison of the intestinal absorption of quercetin, phloretin and their glucosides in rats. J Nutr 131:2109-2114.
12. Boersma MG, van der Woude H, Bogaards J, Boeren S, Vervoort J, Cnubben NH, van Iersel ML, van Bladeren PJ, Rietjens IM. 2002. Regioselectivity of phase II metabolism of luteolin and quercetin by UDP-glucuronosyl transferases. Chem Res Toxicol 15:662-670.
13. Spencer JP, Abd-el-Mohsen MM, Rice-Evans C. 2004. Cellular uptake and metabolism of flavonoids and their metabolites: Implications for their bioactivity. Arch Biochem Biophys 423:148-161.
14. Zhang L, Zuo Z, Lin G. 2007. Intestinal and hepatic glucuronidation of flavonoids. Mol Pharm 4:833-845.
15. Walle T, Otake Y, Brubaker JA, Walle UK, Halushka PV. 2001. Disposition and metabolism of the flavonoid chrysin in normal volunteers. Br J Clin Pharmacol 51:143-146.
16. Setchell KD, Brown NM, Desai P, Zimmer-Nechemias L, Wolfe BE, Brashear WT, Kirschner AS, Cassidy A, Heubi JE. 2001. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr 131:1362S-1375S.
17. Tukey RH, Strassburg CP. 2000. Human UDPglucuronosyltransferases: Metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40:581-616.
18. Kaminsky LS, Zhang QY. 2003. The small intestine as a xenobiotic-metabolizing organ. Drug Metab Dispos 31:1520-1525.
19. Rimbach G, Weinberg PD, de Pascual-Teresa S, Alonso MG, Ewins BA, Turner R, Minihane AM, Botting N, Fairley B, Matsugo S, Uchida Y, Cassidy A. 2004. Sulfation of genistein alters its antioxidant properties and its effect on platelet aggregation and monocyte and endothelial function. Biochim Biophys Acta 1670:229-237.
20. Donnini S, Finetti F, Lusini L, Morbidelli L, Cheynier V, Barron D, Williamson G, Waltenberger J, Ziche M. 2006. Divergent effects of quercetin conjugates on angiogenesis. Br J Nutr 95:1016-1023.
21. Tribolo S, Lodi F, Connor C, Suri S, Wilson VG, Taylor MA, Needs PW, Kroon PA, Hughes DA. 2008. Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells. Atherosclerosis 197:50-56.
22. Yang JH, Hsia TC, Kuo HM, Chao PD, Chou CC, Wei YH, Chung JG. 2006. Inhibition of lung cancer cell growth by quercetin glucuronides via G2/M arrest and induction of apoptosis. Drug Metab Dispos 34:296-304.
23. Harada M, Kan Y, Naoki H, Fukui Y, Kageyama N, Nakai M, Miki W, Kiso Y. 1999. Identification of the major antioxidative metabolites in biological fluids of the rat with ingested (+)-catechin and (-)-epicatechin. Biosci Biotechnol Biochem 63:973-977.
24. Terao J, Yamaguchi S, Shirai M, Miyoshi M, Moon JH, Oshima S, Inakuma T, Tsushida T, Kato Y. 2001. Protection by quercetin and quercetin 3-Obeta-D-glucuronide of peroxynitrite-induced antioxidant consumption in human plasma lowdensity lipoprotein. Free Radic Res 35:925-931.
25. Jovanovich SV, Steenken S, Simic MG, Hara Y. 1998. Flavonoids in health and disease. New York: Marcel Dekker. pp. 137-161.
26. Lambert JD, Sang S, Yang CS. 2007. Biotransformation of green tea polyphenols and the biological activities of those metabolites. Mol Pharm 4:819-825.
27. Setchell KD, Brown NM, Lydeking-Olsen E. 2002. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr 132:3577-3584.
28. Lund TD, Munson DJ, Haldy ME, Setchell KD, Lephart ED, Handa RJ. 2004. Equol is a novel anti-androgen that inhibits prostate growth and hormone feedback. Biol Reprod 70:1188-1195.
29. Di Virgilio AL, Iwami K, Wätjen W, Kahl R, Degen GH. 2004. Genotoxicity of the isoflavones genistein, daidzein and equol in V79 cells. Toxicol Lett 151:151-162.
30. van de Wetering K, Burkon A, Feddema W, Bot A, de Jonge H, Somoza V, Borst P. 2009. Intestinal breast cancer resistance protein (BCRP)/Bcrp1 and multidrug resistance protein 3 (MRP3)/ Mrp3 are involved in the pharmacokinetics of resveratrol. Mol Pharmacol 75:876-885.
31. Chan LM, Lowes S, Hirst BH. 2004. The ABCs of drug transport in intestine and liver: Efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 21:25-51.
32. Krishnamurthy P, Schuetz JD. 2006. Role of ABCG2/BCRP in biology and medicine. Annu Rev Pharmacol Toxicol 46:381-410.
33. Polgar O, Robey RW, Bates SE. 2008. ABCG2: Structure, function and role in drug response. Expert Opin Drug Metab Toxicol 4:1-15.
34. Szakács G, Váradi A, Ozvegy-Laczka C, Sarkadi B. 2008. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today 13:379-393.
35. van Zanden JJ, Wortelboer HM, Bijlsma S, Punt A, Usta M, Bladeren PJ, Rietjens IM, Cnubben NH. 2005. Quantitative structure activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2. Biochem Pharmacol 69:699-708.
36. Wu CP, Calcagno AM, Hladky SB, Ambudkar SV, Barrand MA. 2005. Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5). FEBS J 272:4725-4740.
37. Wesołowska O, Łania-Pietrzak B, Kuzdzał M, Stanczak K, Mosiadz D, Dobryszycki P, Ozyhar A, Komorowska M, Hendrich AB, Michalak K. 2007. Influence of silybin on biophysical properties of phospholipid bilayers. Acta Pharmacol Sin 28: 296-306.
38. van Zanden JJ, van der Woude H, Vaessen J, Usta M, Wortelboer HM, Cnubben NH, Rietjens IM. 2007. The effect of quercetin phase II metabolism on its MRP1 and MRP2 inhibiting potential. Biochem Pharmacol 74:345-351.
39. Zhang L, Lin G, Kovács B, Jani M, Krajcsi P, Zuo Z. 2007. Mechanistic study on the intestinal absorption and disposition of baicalein. Eur J Pharm Sci 31:221-231.
40. Trompier D, Baubichon-Cortay H, Chang XB, Maitrejean M, Barron D, Riordon JR, Di Pietro A. 2003. Multiple flavonoid-binding sites within multidrug resistance protein MRP1. Cell Mol Life Sci 60:2164-2177.
41. Leslie EM, Mao Q, Oleschuk CJ, Deeley RG, Cole SP. 2001. Modulation of multidrug resistance protein 1 (MRP1/ABCC1) transport and ATPase activities by interaction with dietary flavonoids. Mol Pharmacol 59:1171-1180.
42. Leslie EM, Deeley RG, Cole SP. 2003. Bioflavonoid stimulation of glutathione transport by the 190-kDa multidrug resistance protein 1 (MRP1). Drug Metab Dispos 31:11-15.
43. Pérez-Victoria JM, Chiquero MJ, Conseil G, Dayan G, Di Pietro A, Barron D, Castanys S, Gamarro F. 1999. Correlation between the affinity of flavonoids binding to the cytosolic site of Leishmania tropica multidrug transporter and their efficiency to revert parasite resistance to daunomycin. Biochemistry 38:1736-1743.
44. Pérez-Victoria JM, Di Pietro A, Barron D, Ravelo AG, Castanys S, Gamarro F. 2002. Multidrug resistance phenotype mediated by the P-glycoprotein-like transporter in Leishmania: A search for reversal agents. Curr Drug Targets 3:311-333.
45. Conseil G, Decottignies A, Jault JM, Comte G, Barron D, Goffeau A, Di Pietro A. 2000. Prenyl-flavonoids as potent inhibitors of the Pdr5p multidrug ABC transporter from Saccharomyces cerevisiae. Biochemistry 39:6910-6917.
46. Aszalos A. 2008. Role of ATP-binding cassette (ABC) transporters in interactions between natural products and drugs. Curr Drug Metab 9:1010-1018.
47. Hegedus C, Szakács G, Homolya L, Orbán TI, Telbisz A, Jani M, Sarkadi B. 2009. Ins and outs of the ABCG2 multidrug transporter: An update on in vitro functional assays. Adv Drug Deliv Rev 61:47-56.
48. Saito H, Hirano H, Nakagawa H, Fukami T, Oosumi K, Murakami K, Kimura H, Kouchi T, Konomi M, Tao E, Tsujikawa N, Tarui S, Nagakura M, Osumi M, Ishikawa T. 2006. A new strategy of high-speed screening and quantitative structure-activity relationship analysis to evaluate human ATP-binding cassette transporter ABCG2-drug interactions. J Pharmacol Exp Ther 317:1114-1124.
49. van Breemen RB, Li Y. 2005. Caco-2 cell permeability assays to measure drug absorption. Expert Opin Drug Metab Toxicol 1:175-185.
50. Schlatter P, Gutmann H, Drewe J. 2006. Primary porcine proximal tubular cells as a model for transepithelial drug transport in human kidney. Eur J Pharm Sci 28:141-154.
51. Xia CQ, Liu N, Yang D, Miwa G, Gan LS. 2005. Expression, localization, and functional characteristics of breast cancer resistance protein in Caco-2 cells. Drug Metab Dispos 33:637-643.
52. Siissalo S, Laitinen L, Koljonen M, Vellonen KS, Kortejärvi H, Urtti A, Hirvonen J, Kaukonen AM. 2007. Effect of cell differentiation and passage number on the expression of efflux proteins in wild type and vinblastine-induced Caco-2 cell lines. Eur J Pharm Biopharm 67:548-554.
53. Pulido MM, Molina AJ, Merino G, Mendoza G, Prieto JG, Alvarez AI. 2006. Interaction of enro-floxacin with breast cancer resistance protein (BCRP/ABCG2): Influence of flavonoids and role in milk secretion in sheep. J Vet Pharmacol Ther 9:279-287.
54. Cao J, Chen X, Liang J, Yu XQ, Xu AL, Chan E, Wei D, Huang M, Wen JY, Yu XY, Li XT, Sheu FS, Zhou SF. 2007. Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra. Drug Metab Dispos 35:539-553.
55. Wang Y, Cao J, Zeng S. 2005. Involvement of Pglycoprotein in regulating cellular levels of Ginkgo flavonols: Quercetin, kaempferol, and isorhamnetin. J Pharm Pharmacol 57:751-758.
56. Cermak R, Wolffram S. 2006. The potential of flavonoids to influence drug metabolism and pharmacokinetics by local gastrointestinal mechanisms. Curr Drug Metab 7:729-744.
57. Walle UK, French KL, Walgren RA, Walle T. 1999. Transport of genistein-7-glucoside by human intestinal CACO-2 cells: Potential role for MRP2. Res Commun Mol Pathol Pharmacol 103:45-56.
58. Walle UK, Galijatovic A, Walle T. 1999. Transport of the flavonoid chrysin and its conjugated metabolites by the human intestinal cell line Caco-2. Biochem Pharmacol 58:431-438.
59. Walgren RA, Karnaky KJ, Jr., Lindenmayer GE, Walle T. 2000. Efflux of dietary flavonoid quercetin 4'-beta-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistanceassociated protein-2. J Pharmacol Exp Ther 294: 830-836.
60. Juergenliemk G, Boje K, Huewel S, Lohmann C, Galla HJ, Nahrstedt A. 2003. In vitro studies indicate that miquelianin (quercetin 3-O-beta- Dglucuronopyranoside) is able to reach the CNS from the small intestine. Planta Med 69:1013-1017.
61. Hu M, Chen J, Lin H. 2003. Metabolism of flavonoids via enteric recycling: Mechanistic studies of disposition of apigenin in the Caco-2 cell culture model. J Pharmacol Exp Ther 307:314-321.
62. Vaidyanathan JB, Walle T. 2001. Transport and metabolism of the tea flavonoid (-)-epicatechin by the human intestinal cell line Caco-2. Pharm Res 18:1420-1425.
63. Kaldas MI, Walle UK, Walle T. 2003. Resveratrol transport and metabolism by human intestinal Caco-2 cells. J Pharm Pharmacol 55:307-312.
64. Maier-Salamon A, Hagenauer B, Reznicek G, Szekeres T, Thalhammer T, Jäger W. 2008. Metabolism and disposition of resveratrol in the isolated perfused rat liver: Role of Mrp2 in the biliary excretion of glucuronides. J Pharm Sci 97:1615-1628.
65. Cao F, Zhang H, Guo J, Ping Q. 2008. Mrp2-related efflux of scutellarin in the intestinal absorption in rats. Pharmazie 63:75-80.
66. Robey RW, Medina-Pérez WY, Nishiyama K, Lahusen T, Miyake K, Litman T, Senderowicz AM, Ross DD, Bates SE. 2001. Overexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin Cancer Res 7:145-752.
67. Imai Y, Tsukahara S, Asada S, Sugimoto Y. 2004. Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance. Cancer Res 64:4346-4352.
68. Enokizono J, Kusuhara H, Sugiyama Y. 2007. Effect of breast cancer resistance protein (Bcrp/ Abcg2) on the disposition of phytoestrogens. Mol Pharmacol 72:967-975.
69. Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ. 2004. Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic Biol Med 36:592-604.
70. Sesink AL, Arts IC, de Boer VC, Breedveld P, Schellens JH, Hollman PC, Russel FG. 2005. Breast cancer resistance protein (Bcrp1/Abcg2) limits net intestinal uptake of quercetin in rats by facilitating apical efflux of glucuronides. Mol Pharmacol 67:1999-2006.
71. Wang SW, Chen Y, Joseph T, Hu M. 2008. Variable isoflavone content of red clover products affects intestinal disposition of biochanin A, formononetin, genistein, and daidzein. J Altern Complement Med 14:287-297.
72. Brand W, van der Wel PA, Rein MJ, Barron D, Williamson G, van Bladeren PJ, Rietjens IM. 2008. Metabolism and transport of the citrus flavonoid hesperetin in Caco-2 cell monolayers. Drug Metab Dispos 36:1794-1802.
73. Conseil G, Baubichon-Cortay H, Dayan G, Jault JM, Barron D, Di Pietro A. 1998. Flavonoids: A class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein. Proc Natl Acad Sci USA 95:9831-9836.
74. Wang EJ, Barecki-Roach M, Johnson WW. 2002. Elevation of P-glycoprotein function by a catechin in green tea. Biochem Biophys Res Commun 297: 412-428.
75. Jodoin J, Demeule M, Beliveau R. 2002. Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta 1542:149-159.
76. Shapiro AB, Ling V. 1997. Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur J Biochem 250: 130-137.
77. Mitsunaga Y, Takanaga H, Matsuo H, Naito M, Tsuruo T, Ohtani H, Sawada Y. 2000. Effect of bioflavonoids on vincristine transport across blood-brain barrier. Eur J Pharmacol 395:193-201.
78. Di Pietro A, Conseil G, Pérez-Victoria JM, Dayan G, Baubichon-Cortay H, Trompier D, Steinfels E, Jault JM, de Wet H, Maitrejean M, Comte G, Boumendjel A, Mariotte AM, Dumontet C, McIntosh DB, Goffeau A, Castanys S, Gamarro F, Barron D. 2002. Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters. Cell Mol Life Sci 59:307-322.
79. Patel J, Buddha B, Dey S, Pal D, Mitra AK. 2004. In vitro interaction of the HIV protease inhibitor ritonavir with herbal constituents: Changes in P-gp and CYP3A4 activity. Am J Ther 11:262-277.
80. Ji BS, He L. 2007. CJY, an isoflavone, reverses P-glycoprotein-mediated multidrug-resistance in doxorubicin-resistant human myelogenous leukaemia (K562/DOX) cells. J Pharm Pharmacol 59:1011-1015.
81. Yoo HH, Lee M, Chung HJ, Lee SK, Kim DH. 2007. Effects of diosmin, a flavonoid glycoside in citrus fruits, on P-glycoprotein-mediated drug efflux in human intestinal Caco-2 cells. J Agric Food Chem 55:7620-7625.
82. Evans AM. 2000. Influence of dietary components on the gastrointestinal metabolism and transport of drugs. Ther Drug Monit 22:131-136.
83. Ioannides C. 2002. Pharmacokinetic interactions between herbal remedies and medicinal drugs. Xenobiotica 32:451-478.
84. Zhou S, Lim LY, Chowbay B. 2004. Herbal modulation of P-glycoprotein. Drug Metab Rev 36:57-104.
85. Dresser GK, Bailey DG. 2003. The effects of fruit juices on drug disposition: A new model for drug interactions. Eur J Clin Invest 33:10-16.
86. Takanaga H, Ohnishi A, Matsuo H, Sawada Y. 1998. Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in caco-2 cells. Biol Pharm Bull 21:1062-1066.
87. Ikegawa T, Ushigome F, Koyabu N, Morimoto S, Shoyama Y, Naito M, Tsuruo T, Ohtani H, Sawada Y. 2000. Inhibition of P-glycoprotein by orange juice components, polymethoxyflavones in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. Cancer Lett 160:21-28.
88. Takanaga H, Ohnishi A, Yamada S, Matsuo H, Morimoto S, Shoyama Y, Ohtani H, Sawada Y. 2000. Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4. J Pharmacol Exp Ther 293:230-236.
89. Ohtani H, Ikegawa T, Honda Y, Kohyama N, Morimoto S, Shoyama Y, Juichi M, Naito M, Tsuruo T, Sawada Y. 2007. Effects of various methoxyflavones on vincristine uptake and multidrug resistance to vincristine in P-gp-overexpressing K562/ADM cells. Pharm Res 24: 1936-1943.
90. Sergent T, Ribonnet L, Kolosova A, Garsou S, Schaut A, De Saeger S, Van Peteghem C, Larondelle Y, Pussemier L, Schneider YJ. 2008. Molecular and cellular effects of food contaminants and secondary plant components and their plausible interactions at the intestinal level. Food Chem Toxicol 46:813-841.
91. Moon YJ, Wang X, Morris ME. 2006. Dietary flavonoids: Effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro 20:187-210.
92. Li P, Callery PS, Gan LS, Balani SK. 2007. Esterase inhibition by grapefruit juice flavonoids leading to a new drug interaction. Drug Metab Dispos 35:1203-1208.
93. Wacher VJ, Wu CY, Benet LZ. 1995. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 13:129-134.
94. Zhang Y, Benet LZ. 2001. The gut as a barrier to drug absorption: Combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 40:159-168.
95. Cummins CL, Jacobsen W, Christians U, Benet LZ. 2004. CYP3A4-transfected Caco-2 cells as a tool for understanding biochemical absorption barriers: Studies with sirolimus and midazolam. J Pharmacol Exp Ther 308:143-155.
96. Zhang QY, Dunbar D, Ostrowska A, Zeisloft S, Yang J, Kaminsky LS. 1999. Characterization of human small intestinal cytochromes P-450. Drug Metab Dispos 27:804-809.
97. Mouly S, Paine MF. 2003. P-glycoprotein increases from proximal to distal regions of human small intestine. Pharm Res 20:1595-1599.
98. Kim DH, Jung EA, Sohng IS, Han JA, Kim TH, Han MJ. 1998. Intestinal bacterial metabolism of flavonoids and its relation to some biological activities. Arch Pharm Res 21:17-23.
99. De Castro WV, Mertens-Talcott S, Derendorf H, Butterweck V. 2007. Grapefruit juice-drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. J Pharm Sci 96:2808-2817.
100. De Castro WV, Mertens-Talcott S, Derendorf H, Butterweck V. 2008. Effect of grapefruit juice, naringin, naringenin, and bergamottin on the intestinal carrier-mediated transport of talinolol in rats. J Agric Food Chem 56:4845-4849.
101. Eagling VA, Profit L, Back DJ. 1999. Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. Br J Clin Pharmacol 48:543-552.
102. Choi JS, Shin SC. 2005. Enhanced paclitaxel bioavailability after oral coadministration of paclitaxel prodrug with naringin to rats. Int J Pharm 292: 149-156.
103. Choi JS, Han HK. 2005. Enhanced oral exposure of diltiazem by the concomitant use of naringin in rats. Int J Pharm 305:122-128.
104. Zhang S, Morris ME. 2003. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J Pharmacol Exp Ther 304:1258-1267.
105. Peng SX, Ritchie DM, Cousineau M, Danser E, Dewire R, Floden J. 2006. Altered oral bioavailability and pharmacokinetics of P-glycoprotein substrates by coadministration of biochanin A. J Pharm Sci 95:1984-1993.
106. Castro AF, Altenberg GA. 1997. Inhibition of drug transport by genistein in multidrug-resistant cells expressing P-glycoprotein. Biochem Pharmacol 53:89-93.
107. Limtrakul P, Khantamat O, Pintha K. 2005. Inhibition of P-glycoprotein function and expression by kaempferol and quercetin. J Chemother 17:86-95.
108. Li X, Choi JS. 2007. Effect of genistein on the pharmacokinetics of paclitaxel administered orally or intravenously in rats. Int J Pharm 337: 188-193.
109. Phang JM, Poore CM, Lopaczynska J, Yeh GC. 1993. Flavonol stimulated efflux of 7,12-dimethylbenz( a)anthracene in multidrug-resistant breast cancer cells. Cancer Res 53:5977-5981.
110. Critchfield JW, Welsh CJ, Phang JM, Yeh GC. 1994. Modulation of adriamycin accumulation and efflux by flavonoids in HCT-15 colon cells. Activation of P-glycoprotein as a putative mechanism. Biochem Pharmacol 48:1437-1445.
111. Hsiu SL, Hou YC, Wang YH, Tsao CW, Su SF, Chao PD. 2002. Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats. Life Sci 72:227-235.
112. Dupuy J, Larrieu G, Sutra JF, Lespine A, Alvinerie M. 2003. Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: Quercetin. Vet Parasitol 112:337-347.
113. Choi JS, Han HK. 2004. The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. J Pharm Pharmacol 56:1537-1542.
114. Choi JS, Choi HK, Shin SC. 2004. Enhanced bioavailability of paclitaxel after oral coadministration with flavone in rats. Int J Pharm 275:165-170.
115. Wang YH, Chao PD, Hsiu SL, Wen KC, Hou YC. 2004. Lethal quercetin-digoxin interaction in pigs. Life Sci 74:1191-1197.
116. Hodek P, Trefil P, Stiborová M, Hodek P, Trefil P, Stiborová M. 2002. Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450. Chem Biol Interact 139:1-21.
117. Choi BC, Choi JS, Han HK. 2006. Altered pharmacokinetics of paclitaxel by the concomitant use of morin in rats. Int J Pharm 323:81-85.
118. Choi JS, Han HK. 2005. Pharmacokinetic interaction between diltiazem and morin, a flavonoid, in rats. Pharmacol Res 52:386-391.
119. Li X, Yun JK, Choi JS. 2007. Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos 28:151-156.
120. Jäger W, Winter O, Halper B, Salamon A, Sartori M, Gajdzik L, Hamilton G, Theyer G, Graf J, Thalhammer T. 1997. Modulation of liver canalicular transport processes by the tyrosine-kinase inhibitor genistein: Implications of genistein metabolism in the rat. Hepatology 26:1467-1476.
121. Sergent T, Garsou S, Schaut A, De Saeger S, Pussemier L, Van Peteghem C, Larondelle Y, Schneider YJ. 2005. Differential modulation of ochratoxin A absorption across Caco-2 cells by dietary polyphenols, used at realistic intestinal concentrations. Toxicol Lett 159:60-70.
122. Schrickx J, Lektarau Y, Fink-Gremmels J. 2006. Ochratoxin A secretion by ATP-dependent membrane transporters in Caco-2 cells. Arch Toxicol 80:243-249.
123. Williamson G, Aeberli I, Miguet L, Zhang Z, Sanchez MB, Crespy V, Barron D, Needs P, Kroon PA, Glavinas H, Krajcsi P, Grigorov M. 2007. Interaction of positional isomers of quercetin glucuronides with the transporter ABCC2 (cMOAT, MRP2). Drug Metab Dispos 35:1262-1268.
124. Jäger W, Gehring E, Hagenauer B, Aust S, Senderowicz A, Thalhammer T. 2003. Biliary excretion of flavopiridol and its glucuronides in the isolated perfused rat liver: Role of multidrug resistance protein 2 (Mrp2). Life Sci 73:2841-2854.
125. Zelcer N, Huisman MT, Reid G, Wielinga P, Breedveld P, Kuil A, Knipscheer P, Schellens JH, Schinkel AH, Borst P. 2003. Evidence for two interacting ligand binding sites in human multidrug resistance protein 2 (ATP binding cassette C2). J Biol Chem 278:23538-23544.
126. Zhang S, Yang X, Morris ME. 2004. Combined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)-mediated transport. Pharm Res 21:1263-1273.
127. Zhang S, Yang X, Coburn RA, Morris ME. 2005. Structure activity relationships and quantitative structure activity relationships for the flavonoidmediated inhibition of breast cancer resistance protein. Biochem Pharmacol 70:627-639.
128. Ahmed-Belkacem A, Pozza A, Muñoz-Martínez F, Bates SE, Castanys S, Gamarro F, Di Pietro A, Pérez-Victoria JM. 2005. Flavonoid structureactivity studies identify 6-prenylchrysin and tectochrysin as potent and specific inhibitors of breast cancer resistance protein ABCG2. Cancer Res 65:4852-48560.
129. Takahata T, Ookawa K, Suto K, Tanaka M, Yano H, Nakashima O, Kojiro M, Tamura Y, Tateishi T, Sakata Y, Fukuda S. 2008. Chemosensitivity determinants of irinotecan hydrochloride in hepatocellular carcinoma cell lines. Basic Clin Pharmacol Toxicol 102:399-407.
130. Yoshikawa M, Ikegami Y, Sano K, Yoshida H, Mitomo H, Sawada S, Ishikawa T. 2004. Transport of SN-38 by the wild type of human ABC transporter ABCG2 and its inhibition by quercetin, a natural flavonoid. J Exp Ther Oncol 4:25-35.
131. Cooray HC, Janvilisri T, van Veen HW, Hladky SB, Barrand M. 2004. Interaction of the breast cancer resistance protein with plant polyphenols. Biochem Biophys Res Commun 317:269-275.
132. Katayama K, Masuyama K, Yoshioka S, Hasegawa H, Mitsuhashi J, Sugimoto Y. 2007. Flavonoids inhibit breast cancer resistance protein-mediated drug resistance: Transporter speci-ficity and structure-activity relationship. Cancer Chemother Pharmacol 60:789-797.
133. Zhang S, Wang X, Sagawa K, Morris ME. 2005. Flavonoids chrysin and benzoflavone, potent BCRP inhibitors, have no significant effect on topotecan pharmacokinetics in rats or Mdr1a/1b (-/-) mice. Drug Metab Dispos 33:341-348.
134. Wang X, Morris ME. 2007. Effects of the flavonoid chrysin on nitrofurantoin pharmacokinetics in rats: Potential involvement of ABCG2. Drug Metab Dispos 35:268-274.
135. Wang X, Morris ME. 2008. Pharmacokinetics and bioavailability of the flavonoid 7,8-benzoflavone in rats. J Pharm Sci 97:4546-4556.
136. Clark R, Kerr ID, Callaghan R. 2006. Multiple drug binding sites on the R482G isoform of the ABCG2 transporter. Br J Pharmacol 149:506-515.
137. Setchell KD, Brown NM, Desai P, Zimmer-Nechemias L, Wolfe BE, Brashear WT, Kirschner AS, Cassidy A, Heubi JE. 2001. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr 131:1362S-1375S.
138. Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, van der Valk MA, Voordouw AC, Spits H, van Tellingen O, Zijlmans JM, Fibbe WE, Borst P. 1997. Normal viability and altered pharmacokinetics in mice lacking mdr1- type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 94:4028-4033.
139. Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, Plosch T, Kuipers F, Elferink RP, Rosing H, Beijnen JH, Schinkel AH. 2002. The breast cancer resistance protein protects against a major chlorophyllderived dietary phototoxin and protoporphyria. Proc Natl Acad Sci USA 99:15649-15654.
140. Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM. 1999. Inhibition of P-glycoproteinmediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 99:552-557.
141. Verschraagen M, Koks CH, Schellens JH, Beijnen JH. 1999. P-glycoprotein system as a determinant of drug interactions: The case of digoxin-verapamil. Pharmacol Res 40:301-306.
142. Huls M, Kramers C, Levtchenko EN, Wilmer MJ, Dijkman HB, Kluijtmans LA, van der Hoorn JW, Russel FG, Masereeuw R. 2007. P-glycoproteindeficient mice have proximal tubule dysfunction but are protected against ischemic renal injury. Kidney Int 72:1233-1241.
143. Huls M, Russel FG, Masereeuw R. 2009. The role of ATP binding cassette transporters in tissue defense and organ regeneration. J Pharmacol Exp Ther 328:3-9.
144. Schutte ME, Boersma MG, Verhallen DA, Groten JP, Rietjens IM. 2008. Effects of flavonoid mixtures on the transport of 2-amino-1-methyl-6- phenylimidazo[ 4,5-b]pyridine (PhIP) through Caco-2 monolayers: An in vitro and kinetic modeling approach to predict the combined effects on transporter inhibition. Food Chem Toxicol 46:557-566.
145. Brand W, Schutte ME, Williamson G, van Zanden JJ, Cnubben NH, Groten JP, van Bladeren PJ, Rietjens IM. 2006. Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients. Biomed Pharmacother 60:508-519.
146. Lohner K, Schnäbele K, Daniel H, Oesterle D, Rechkemmer G, Göttlicher M, Wenzel U. 2007. Flavonoids alter P-gp expression in intestinal epithelial cells in vitro and in vivo. Mol Nutr Food Res 51:293-300.
147. Sugatani J, Yamakawa K, Tonda E, Nishitani S, Yoshinari K, Degawa M, Abe I, Noguchi H, Miwa M. 2004. The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics. Biochem Pharmacol 67:989-1000.
148. Bock KW, Eckle T, Ouzzine M, Fournel-Gigleux S. 2000. Coordinate induction by antioxidants of UDP-glucuronosyltransferase UGT1A6 and the apical conjugate export pump MRP2 (multidrug resistance protein 2) in Caco-2 cells. Biochem Pharmacol 59:467-470.
149. Vernhet L, Séité MP, Allain N, Guillouzo A, Fardel O. 2001. Arsenic induces expression of the multidrug resistance-associated protein 2 (MRP2) gene in primary rat and human hepatocytes. J Pharmacol Exp Ther 298:234-239.
150. Ebert B, Seidel A, Lampen A. 2007. Phytochemicals induce BCRP in Caco-2 cells and enhance the transport of benzo[a]pyrene-3-sulfate. Toxicol Sci 96:227-236.
151. Formica JV, Regelson W. 1995. Review of the biology of Quercetin and related bioflavonoids. Food Chem Toxicol 33:1061-1080.
152. Moon YJ, Morris ME. 2007. Pharmacokinetics and bioavailability of the bioflavonoid biochanin A: Effects of quercetin and EGCG on biochanin A disposition in rats. Mol Pharm 4:865-872.
153. Fritz WA, Coward L, Wang J, Lamartiniere C. 1998. Dietary genistein: Perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat. Carcinogenesis 19:2151-2158.
154. Chang HC, Churchwell MI, Delclos KB, Newbold RR, Doerge DR. 2000. Mass spectrometric determination of Genistein tissue distribution in diet-exposed Sprague-Dawley rats. J Nutr 130: 1963-1970.
155. Youdim KA, Spencer JP, Schroeter H, Rice-Evans C. 2002. Dietary flavonoids as potential neuroprotectants. Biol Chem 383:503-519.
156. Maubach J, Bracke ME, Heyerick A, Depypere HT, Serreyn RF, Mareel MM, De Keukeleire D. 2003. Quantitation of soy-derived phytoestrogens in human breast tissue and biological fluids by high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 784: 137-144.
157. Wang X, Wolkoff AW, Morris ME. 2005. Flavonoids as a novel class of human organic aniontransporting polypeptide OATP1B1 (OATP-C) modulators. Drug Metab Dispos 33:1666-1672.
158. Fuchikami H, Satoh H, Tsujimoto M, Ohdo S, Ohtani H, Sawada Y. 2006. Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos 34:577-582.
159. Shim CK, Cheon EP, Kang KW, Seo KS, Han HK. 2007. Inhibition effect of flavonoids on monocarboxylate transporter 1 (MCT1) in Caco-2 cells. J Pharm Pharmacol 59:1515-1519.
160. Hong SS, Seo K, Lim SC, Han HK. 2007. Interaction characteristics of flavonoids with human organic anion transporter 1 (hOAT1) and 3 (hOAT3). Pharmacol Res 56:468-473.
161. Yu Z, Fong WP, Cheng CH. 2007. Morin (3,5,7,2′,4′- pentahydroxyflavone) exhibits potent inhibitory actions on urate transport by the human urate anion transporter (hURAT1) expressed in human embryonic kidney cells. Drug Metab Dispos 35:981-986.
162. Chen CH, Hsu HJ, Huang YJ, Lin CJ. 2007. Interaction of flavonoids and intestinal facilitated glucose transporters. Planta Med 73:348-354.