Phytochemistry Reviews

, Volume 14, Issue 2, pp 233–272 | Cite as

Flavonoid compounds as reversal agents of the P-glycoprotein-mediated multidrug resistance: biology, chemistry and pharmacology

  • Ana Ferreira
  • Sarah Pousinho
  • Ana Fortuna
  • Amílcar Falcão
  • Gilberto Alves


Multidrug resistance (MDR) represents one of the major problems in pharmacotherapy of important diseases (e.g., cancer, epilepsy). Although many factors may contribute to the development of MDR phenotype, the increased expression and/or functional activity of P-glycoprotein (P-gp; active drug efflux transporter) across the cell membrane has been recognized as the main one. Therefore, a great attention has been given to the search of P-gp inhibitors as therapeutic agents to reverse the MDR mediated by P-gp. Since the chemical entities identified over the last three decades as potential P-gp inhibitors did not show suitable pharmacological properties, more recently herbal components, such as flavonoid compounds, have gained a great interest as safe P-gp inhibitors. The interest in flavonoids as P-gp inhibitors is increasing due to their potential favourable characteristics, including selectivity and non-cytotoxic effects. Flavonoids integrate the third-generation non-pharmaceutical category of P-gp inhibitors, and some of them exhibited effects comparable to those of the classic P-gp inhibitors. In fact, some flavonoids found in foods and beverages of herbal origin appear to be quite promising to inhibit the P-gp–mediated drug efflux, indicating their potential value to enhance the systemic/cellular bioavailability of P-gp drug substrates when administrated in co-therapy. This review paper summarizes the current evidence of P-gp inhibitory effects produced by flavonoids, taking into account studies performed in cell-based in vitro models, in vivo animal models and clinical trials.


Flavonoids P-glycoprotein inhibition Drug efflux Multidrug resistance 



Adenosine triphosphate (ATP)-binding cassette


Area under the concentration–time curve


Breast cancer resistance protein


Total body clearance


Peak concentration


Central nervous system


Cytochrome P450




Multidrug resistance


Multidrug resistance-associated protein


Nucleotide-binding domain




Transmembrane α-helix segments


Transmembrane domain



The authors thank the support of Fundação para a Ciência e a Tecnologia (FCT, Portugal) through the fellowship SFHR/BD/84936/2012, involving the POPH—QREN which is co-funded by FSE and MEC. The authors also thank the funding through the Strategic Project PEst-C/SAU/UI0709/2011.

Conflict of interest

The authors have declared no conflict of interest.


  1. Ali H-A, Chowdhury AKA, Rahman AKM et al (2008) Pachypodol, a flavonol from the leaves of Calycopteris floribunda, inhibits the growth of CaCo-2 colon cancer cell line in vitro. Phytother Res 22:1684–1687PubMedGoogle Scholar
  2. Alonso-Castro AJ, Ortiz-Sánchez E, García-Regalado A et al (2013) Kaempferitrin induces apoptosis via intrinsic pathway in HeLa cells and exerts antitumor effects. J Ethnopharmacol 145:476–489PubMedGoogle Scholar
  3. Alvarez AI, Real R, Pérez M et al (2010) Modulation of the activity of ABC transporters (P-Glycoprotein, MRP2, BCRP) by flavonoids and drug response. J Pharm Sci 99:598–617PubMedGoogle Scholar
  4. Amin ML (2013) P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights 7:27–34PubMedCentralPubMedGoogle Scholar
  5. An G, Morris ME (2010) Effects of the isoflavonoid biochanin A on the transport of mitoxantrone in vitro and in vivo. Biopharm Drug Dispos 31:340–350PubMedGoogle Scholar
  6. Aszalos A (2008) Role of ATP-binding cassette (ABC) transporters in interactions between natural products and drugs. Curr Drug Metab 9:1010–1018PubMedGoogle Scholar
  7. Badhan R, Penny J (2006) In silico modelling of the interaction of flavonoids with human P-glycoprotein nucleotide-binding domain. Eur J Med Chem 41:285–295PubMedGoogle Scholar
  8. Balayssac D, Authier N, Cayre A, Coudore F (2005) Does inhibition of P-glycoprotein lead to drug–drug interactions? Toxicol Lett 156:319–329PubMedGoogle Scholar
  9. Bansal T, Awasthi A, Jaggi M et al (2008) Pre-clinical evidence for altered absorption and biliary excretion of irinotecan (CPT-11) in combination with quercetin: possible contribution of P-glycoprotein. Life Sci 83:250–259PubMedGoogle Scholar
  10. Bansal T, Jaggi M, Khar RK, Talegaonkar S (2009) Emerging significance of flavonoids as P-glycoprotein inhibitors in cancer chemotherapy. J Pharm Pharm Sci 12:46–78PubMedGoogle Scholar
  11. Barron D, Di Pietro A, Dumontet C, Mcintosh DB (2003) Isoprenoid flavonoids are new leads in the modulation of chemoresistance. Phytochem Rev 1:325–332Google Scholar
  12. Bellamy WT (1996) P-glycoproteins and multidrug resistance. Annu Rev Pharmacol Toxicol 36:161–183PubMedGoogle Scholar
  13. Bois F, Beney C, Boumendjel A et al (1998) Halogenated chalcones with high-affinity binding to P-glycoprotein: potential modulators of multidrug resistance. J Med Chem 41:4161–4164PubMedGoogle Scholar
  14. Bois F, Boumendjel A, Mariotte AM et al (1999) Synthesis and biological activity of 4-alkoxy chalcones: potential hydrophobic modulators of P-glycoprotein-mediated multidrug resistance. Bioorg Med Chem 7:2691–2695PubMedGoogle Scholar
  15. Borska S, Sopel M, Chmielewska M et al (2010) Quercetin as a potential modulator of P-glycoprotein expression and function in cells of human pancreatic carcinoma line resistant to daunorubicin. Molecules 15:857–870PubMedGoogle Scholar
  16. Boumendjel A, Di Pietro A, Dumontet C, Barron D (2002) Recent advances in the discovery of flavonoids and analogs with high-affinity binding to P-glycoprotein responsible for cancer cell multidrug resistance. Med Res Rev 22:512–529PubMedGoogle Scholar
  17. Brand W, Schutte ME, Williamson G et al (2006) Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients. Biomed Pharmacother 60:508–519PubMedGoogle Scholar
  18. Brandt C, Bethmann K, Gastens AM, Löscher W (2006) The multidrug transporter hypothesis of drug resistance in epilepsy: proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis 24:202–211PubMedGoogle Scholar
  19. Breier A, Gibalova L, Seres M et al (2013) New insight into p-glycoprotein as a drug target. Anticancer Agents Med Chem 13:159–170PubMedGoogle Scholar
  20. Buer CS, Imin N, Djordjevic MA (2010) Flavonoids: new roles for old molecules. J Integr Plant Biol 52:98–111PubMedGoogle Scholar
  21. Cassidy CE, Setzer WN (2010) Cancer-relevant biochemical targets of cytotoxic Lonchocarpus flavonoids: a molecular docking analysis. J Mol Model 16:311–326PubMedGoogle Scholar
  22. Castro AF, Altenberg GA (1997) Inhibition of drug transport by genistein in multidrug-resistant cells expressing P-glycoprotein. Biochem Pharmacol 53:89–93Google Scholar
  23. Castro WVDE, Mertens-Talcott S, Derendorf H (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 96:2808–2817PubMedGoogle Scholar
  24. Chan LMS, 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 21:25–51PubMedGoogle Scholar
  25. Chan K-F, Zhao Y, Chow TWS et al (2009) Flavonoid dimers as bivalent modulators for p-glycoprotein-based multidrug resistance: structure-activity relationships. ChemMedChem 4:594–614PubMedGoogle Scholar
  26. Chang X (2007) A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1. Cancer Metastasis Rev 26:15–37PubMedGoogle Scholar
  27. Chang C, Bahadduri PM, Polli JE et al (2006) Rapid identification of P-glycoprotein substrates and inhibitors. Drug Metab Dispos 34:1976–1984PubMedGoogle Scholar
  28. Chen C, Zhou J, Ji C (2010) Quercetin: a potential drug to reverse multidrug resistance. Life Sci 87:333–338PubMedGoogle Scholar
  29. Chieli E, Romiti N, Rodeiro I, Garrido G (2009) In vitro effects of Mangifera indica and polyphenols derived on ABCB1/P-glycoprotein activity. Food Chem Toxicol 47:2703–2710PubMedGoogle Scholar
  30. Cho Y-A, Choi D-H, Choi J-S (2009) Effect of hesperidin on the oral pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats. J Pharm Pharmacol 61:825–829PubMedGoogle Scholar
  31. Cho Y-A, Choi J-S, Burm J-P (2011) Effects of the antioxidant baicalein on the pharmacokinetics of nimodipine in rats: a possible role of P-glycoprotein and CYP3A4 inhibition by baicalein. Pharmacol Rep 63:1066–1073PubMedGoogle Scholar
  32. Choi J-S, Burm JP (2006) Enhanced nimodipine bioavailability after oral administration of nimodipine with morin, a flavonoid, in rabbits. Arch Pharm Res 29:333–338PubMedGoogle Scholar
  33. Choi J-S, Han H-K (2005) Pharmacokinetic interaction between diltiazem and morin, a flavonoid, in rats. Pharmacol Res 52:386–391PubMedGoogle Scholar
  34. Choi J-S, Kang KW (2008) Enhanced tamoxifen bioavailability after oral administration of tamoxifen in rats pretreated with naringin. Arch Pharm Res 31:1631–1636PubMedGoogle Scholar
  35. Choi J-S, Li X (2005) Enhanced diltiazem bioavailability after oral administration of diltiazem with quercetin to rabbits. Int J Pharm 297:1–8PubMedGoogle Scholar
  36. Choi J-S, Choi H-K, Shin S-C (2004a) Enhanced bioavailability of paclitaxel after oral coadministration with flavone in rats. Int J Pharm 275:165–170PubMedGoogle Scholar
  37. Choi J-S, Jo B-W, Kim Y-C (2004b) Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin. Eur J Pharm Biopharm 57:313–318Google Scholar
  38. Choi B-C, Choi J-S, Han H-K (2006) Altered pharmacokinetics of paclitaxel by the concomitant use of morin in rats. Int J Pharm 323:81–85PubMedGoogle Scholar
  39. Choi D-H, Li C, Choi J-S (2010) Effects of myricetin, an antioxidant, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats: possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P-glycoprotein inhibition by myricetin. J Pharm Pharmacol 62:908–914PubMedGoogle Scholar
  40. Choi J-S, Piao Y-J, Kang KW (2011a) Effects of quercetin on the bioavailability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition by quercetin. Arch Pharm Res 34:607–613PubMedGoogle Scholar
  41. Choi S-J, Shin S-C, Choi J-S (2011b) Effects of myricetin on the bioavailability of doxorubicin for oral drug delivery in rats: possible role of CYP3A4 and P-glycoprotein inhibition by myricetin. Arch Pharm Res 34:309–315Google Scholar
  42. Chokchaisiri R, Suaisom C, Sriphota S et al (2009) Bioactive flavonoids of the flowers of Butea monosperma. Chem Pharm Bull (Tokyo) 57:428–432Google Scholar
  43. Chung SY, Sung MK, Kim NH et al (2005) Inhibition of P-glycoprotein by natural products in human breast cancer cells. Arch Pharm Res 28:823–828PubMedGoogle Scholar
  44. Chung SY, Jang DS, Han A et al (2007) Modulation of P-glycoprotein-mediated resistance by kaempferol derivatives isolated from Zingiber zerumbet. Phytother Res 21:565–569Google Scholar
  45. Coley HM (2010) Overcoming multidrug resistance in cancer: clinical studies of p-glycoprotein inhibitors. Methods Mol Biol 596:341–358PubMedGoogle Scholar
  46. Comte G, Daskiewicz JB, Bayet C et al (2001) C-Isoprenylation of flavonoids enhances binding affinity toward P-glycoprotein and modulation of cancer cell chemoresistance. J Med Chem 44:763–768PubMedGoogle Scholar
  47. Conseil G, Baubichon-Cortay H, Dayan G et al (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 95:9831–9836PubMedCentralPubMedGoogle Scholar
  48. Cook N, Samman S (1996) Flavonoids: chemistry, metabolism, cardioprotective effects, and dietary sources. J Nutr Biochem 7:66–76Google Scholar
  49. Corea G, Di Pietro A, Dumontet C et al (2009) Jatrophane diterpenes from Euphorbia spp. as modulators of multidrug resistance in cancer therapy. Phytochem Rev 8:431–447Google Scholar
  50. Crozier A, Jaganath IB, Clifford MN (2009) Dietary phenolics: chemistry, bioavailability and effects on health. Nat Prod Rep 26:1001–1043PubMedGoogle Scholar
  51. Dantzig AH, de Alwis DP, Burgess M (2003) Considerations in the design and development of transport inhibitors as adjuncts to drug therapy. Adv Drug Deliv Rev 55:133–150PubMedGoogle Scholar
  52. 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 56:4840–4845PubMedGoogle Scholar
  53. De Wet H, McIntosh DB, Conseil G et al (2001) Sequence requirements of the ATP-binding site within the C-terminal nucleotide-binding domain of mouse P-glycoprotein: structure-activity relationships for flavonoid binding. Biochemistry 40:10382–10391PubMedGoogle Scholar
  54. Deeley RG, Westlake C, Cole SPC (2006) Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev 86:849–899PubMedGoogle Scholar
  55. Deferme S, Augustijns P (2003) The effect of food components on the absorption of P-gp substrates: a review. J Pharm Pharmacol 55:153–162PubMedGoogle Scholar
  56. Del Amo EM, Heikkinen AT, Mönkkönen J (2009) In vitro-in vivo correlation in P-glycoprotein mediated transport in intestinal absorption. Eur J Pharm Sci 36:200–211PubMedGoogle Scholar
  57. Di Pietro A, Conseil G, Pérez-victoria JM et al (2002) Cellular and molecular life sciences modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters. Cell Mol Life Sci 59:307–322PubMedGoogle Scholar
  58. Dinis-Oliveira RJ, Remião F, Duarte J et al (2006) P-glycoprotein induction: an antidotal pathway for paraquat-induced lung toxicity. Free Radic Biol Med 41:1213–1224PubMedGoogle Scholar
  59. Doran A, Obach RS, Smith BJ et al (2005) The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos 33:165–174PubMedGoogle Scholar
  60. Du G-J, Zhang Z, Wen X-D et al (2012) Epigallocatechin Gallate (EGCG) is the most effective cancer chemopreventive polyphenol in green tea. Nutrients 4:1679–1691PubMedCentralPubMedGoogle Scholar
  61. Fang S-H, Hou Y-C, Chao P-DL (2005) Pharmacokinetic and pharmacodynamic interactions of morin and cyclosporin. Toxicol Appl Pharmacol 205:65–70PubMedGoogle Scholar
  62. Fernández SP, Wasowski C, Paladini AC, Marder M (2005) Synergistic interaction between hesperidin, a natural flavonoid, and diazepam. Eur J Pharmacol 512:189–198PubMedGoogle Scholar
  63. Fortuna A, Alves G, Falcão A (2011) In vitro and in vivo relevance of the P-glycoprotein probe substrates in drug discovery and development: focus on rhodamine 123, digoxin and talinolol. J Bioequiv Availab 01:1–23Google Scholar
  64. Fromm MF (2004) Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol Sci 25:423–429PubMedGoogle Scholar
  65. Gazák R, Walterová D, Kren V (2007) Silybin and silymarin-new and emerging applications in medicine. Curr Med Chem 14:315–338PubMedGoogle Scholar
  66. Giacomini KM, Huang S-M, Tweedie DJ et al (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236PubMedGoogle Scholar
  67. Girardin F (2006) Membrane transporter proteins: a challenge for CNS drug development. Dialogues Clin Neurosci 8:311–321PubMedCentralPubMedGoogle Scholar
  68. Go WJ, Ryu JH, Qiang F, Han H-K (2009) Evaluation of the flavonoid oroxylin A as an inhibitor of P-glycoprotein-mediated cellular efflux. J Nat Prod 72:1616–1619PubMedGoogle Scholar
  69. Guidance for Industry (2006) Drug interaction studies: study design, data analysis, and implications for dosing and labeling. U.S. Department of Health and Human Services, FDA, CDER, CBERGoogle Scholar
  70. Hadjeri M, Barbier M, Ronot X et al (2003) Modulation of P-glycoprotein-mediated multidrug resistance by flavonoid derivatives and analogues. J Med Chem 46:2125–2131PubMedGoogle Scholar
  71. Harborne JB (1962) Plant polyphenols. 5: occurrence of azalein and related pigments in flowers of Plumbago and Rhododendron species. Arch Biochem Biophys 96:171–178PubMedGoogle Scholar
  72. Hasegawa M, Shirato T (2002) Two new flavonoid glycosides from the leaves of Phellodendron amurense Ruprecht. J Am Chem Soc 75:5507–5511Google Scholar
  73. Hendrich AB (2006) Flavonoid-membrane interactions: possible consequences for biological effects of some polyphenolic compounds. Acta Pharmacol Sin 27:27–40PubMedGoogle Scholar
  74. Hennessy M, Spiers JP (2007) A primer on the mechanics of P-glycoprotein the multidrug transporter. Pharmacol Res 55:1–15PubMedGoogle Scholar
  75. Horowitz RM, Gentili B (1960) Flavonoids of the Ponderosa lemon. Nature 185:319PubMedGoogle Scholar
  76. Hsiu S-L, Hou Y-C, Wang Y-H et al (2002) Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats. Life Sci 72:227–235PubMedGoogle Scholar
  77. Huisman MT, Smit JW, Wiltshire HR et al (2003) Assessing safety and efficacy of directed P-glycoprotein inhibition to improve the pharmacokinetic properties of saquinavir coadministered with ritonavir. J Pharmacol Exp Ther 304:596–602PubMedGoogle Scholar
  78. Ikegawa T, Ushigome F, Koyabu N, Morimoto S (2000) Inhibition of P-glycoprotein by orange juice components, polymethoxyflavones in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. Cancer Lett 160:21–28Google Scholar
  79. Jäger AK, Saaby L (2011) Flavonoids and the CNS. Molecules 16:1471–1485PubMedGoogle Scholar
  80. Jeong J-M, Choi C-H (2007) Enhancement of paclitacel transport and cytotoxicity by 7,3’,4’-trimethoxyflavone, a P-glycoprotein inhibitor. J Pharm Pharm Sci 10:547–553Google Scholar
  81. Jodoin J, Demeule M, Beliveau R (2002) Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta 1542:149–159PubMedGoogle Scholar
  82. Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152–162PubMedGoogle Scholar
  83. Katiyar SK, Meleth S, Sharma SD (2008) Silymarin, a flavonoid from milk thistle (Silybum marianum L.), inhibits UV-induced oxidative stress through targeting infiltrating CD11b+ cells in mouse skin. Photochem Photobiol 84:266–271PubMedCentralPubMedGoogle Scholar
  84. Kellenberger E, Kuhn I, Schuber F, Muller-Steffner H (2011) Flavonoids as inhibitors of human CD38. Bioorg Med Chem Lett 21:3939–3942PubMedGoogle Scholar
  85. Kemper EM, van Zandbergen AE, Cleypool C et al (2003) Increased penetration of paclitaxel into the brain by inhibition of P-Glycoprotein. Clin Cancer Res 9:2849–2855PubMedGoogle Scholar
  86. Keung WM, Vallee BL (1993) Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase. Proc Natl Acad Sci USA 90:1247–1251PubMedCentralPubMedGoogle Scholar
  87. Khan IA, Avery MA, Burandt CL et al (2000) Antigiardial activity of isoflavones from Dalbergia frutescens bark. J Nat Prod 63:1414–1416PubMedGoogle Scholar
  88. Khantamat O, Chaiwangyen W, Porn-ngarm L (2004) Screening of flavonoids for their potential inhibitory effect on p-glycoprotein activity in human cervical carcinoma KB cells. Chiang Mai Med Bull 43:45–56Google Scholar
  89. Kim D-H, Na H-K, Oh TY et al (2004) Eupatilin, a pharmacologically active flavone derived from Artemisia plants, induces cell cycle arrest in ras-transformed human mammary epithelial cells. Biochem Pharmacol 68:1081–1087PubMedGoogle Scholar
  90. Kim K-A, Park P-W, Park J-Y (2009) Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein, in healthy volunteers. Eur J Clin Pharmacol 65:609–614PubMedGoogle Scholar
  91. Kim YH, Lee YS, Choi EM (2010) Chrysoeriol isolated from Eurya cilliata leaves protects MC3T3-E1 cells against hydrogen peroxide-induced inhibition of osteoblastic differentiation. J Appl Toxicol 30:666–673PubMedGoogle Scholar
  92. Kitagawa S (2006) Inhibitory effects of polyphenols on p-glycoprotein-mediated transport. Biol Pharm Bull 29:1–6PubMedGoogle Scholar
  93. Kitagawa S, Nabekura T, Kamiyama S (2004) Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells. J Pharm Pharmacol 56:1001–1005Google Scholar
  94. Kitagawa S, Nabekura T, Takahashi T et al (2005) Structure-activity relationships of the inhibitory effects of flavonoids on P-glycoprotein-mediated transport in KB-C2 cells. Biol Pharm Bull 28:2274–2278PubMedGoogle Scholar
  95. Krishna R, Mayer LD (2000) Multidrug resistance (MDR) in cancer: mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 11:265–283PubMedGoogle Scholar
  96. Kubota H, Ishihara H, Langmann T et al (2006) Distribution and functional activity of P-glycoprotein and multidrug resistance-associated proteins in human brain microvascular endothelial cells in hippocampal sclerosis. Epilepsy Res 68:213–228PubMedGoogle Scholar
  97. Kumar G, Karthik L, Rao KVB (2013) Phytochemical composition and in vitro antioxidant activity of aqueous extract of Aerva lanata (L.) Juss. ex Schult. Stem (Amaranthaceae). Asian Pac J Trop Med 6:180–187PubMedGoogle Scholar
  98. Kwan P, Brodie MJ (2005) Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia 46:224–235PubMedGoogle Scholar
  99. Lam IK, Alex D, Wang Y-H et al (2012) In vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: identifying sinensetin as a novel antiangiogenesis agent. Mol Nutr Food Res 56:945–956PubMedGoogle Scholar
  100. Lazarowski A, Czornyj L, Lubienieki F et al (2007) ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia 48(Suppl 5):140–149PubMedGoogle Scholar
  101. Lee C-K, Choi J-S (2010) Effects of silibinin, inhibitor of CYP3A4 and P-glycoprotein in vitro, on the pharmacokinetics of paclitaxel after oral and intravenous administration in rats. Pharmacology 85:350–356PubMedGoogle Scholar
  102. Ley JP, Krammer G, Reinders G et al (2005) Evaluation of bitter masking flavanones from Herba Santa (Eriodictyon californicum (H. and A.) Torr., Hydrophyllaceae). J Agric Food Chem 53:6061–6066PubMedGoogle Scholar
  103. Li X, Choi J-S (2007) Effect of genistein on the pharmacokinetics of paclitaxel administered orally or intravenously in rats. Int J Pharm 337:188–193PubMedGoogle Scholar
  104. Li C, Choi JS (2008) Effects of epigallocatechin gallate on the bioavailability and pharmacokinetics of diltiazem in rats. Pharmazie 63:815–818PubMedGoogle Scholar
  105. Li X, Choi J-S (2009) Effects of quercetin on the pharmacokinetics of Etoposide after oral or intravenous administration of etoposide in rats. Anticancer Res 29:1411–1415PubMedGoogle Scholar
  106. Li X, Yun J-K, Choi J-S (2007) Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos 28:151–156PubMedGoogle Scholar
  107. Li C, Li X, Choi J-S (2009) Enhanced bioavailability of etoposide after oral or intravenous administration of etoposide with kaempferol in rats. Arch Pharm Res 32:133–138PubMedGoogle Scholar
  108. Li C, Kim M, Choi H, Choi J (2011) Effects of baicalein on the pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats: possible role of cytochrome P450 3A4 and P-glycoprotein inhibition by baicalein. Arch Pharm Res 34:1965–1972PubMedGoogle Scholar
  109. Lim S-C, Choi J-S (2006) Effects of naringin on the pharmacokinetics of intravenous paclitaxel in rats. Biopharm Drug Dispos 27:443–447PubMedGoogle Scholar
  110. Lin JH (2003) Drug–drug interaction mediated by inhibition and induction of P-glycoprotein. Adv Drug Deliv Rev 55:53–81PubMedGoogle Scholar
  111. Lin JH, Yamazaki M (2003) Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42:59–98PubMedGoogle Scholar
  112. Ling V (1997) Multidrug resistance: molecular mechanisms and clinical relevance. Cancer Chemother Pharmacol 40(Suppl):S3–S8PubMedGoogle Scholar
  113. Linnet K, Ejsing TB (2008) A review on the impact of P-glycoprotein on the penetration of drugs into the brain: focus on psychotropic drugs. Eur Neuropsychopharmacol 18:157–169PubMedGoogle Scholar
  114. Lohner K, Schnäbele K, Daniel H et al (2007) Flavonoids alter P-gp expression in intestinal epithelial cells in vitro and in vivo. Mol Nutr Food Res 51:293–300PubMedGoogle Scholar
  115. Löscher W, Potschka H (2002a) Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther 301:7–14PubMedGoogle Scholar
  116. Löscher W, Potschka H (2002b) Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 76:22–76Google Scholar
  117. Löscher W, Potschka H (2005) Blood-brain barrier active efflux transporters: aTP-binding cassette gene family. NeuroRx 2:86–98PubMedCentralPubMedGoogle Scholar
  118. Makino T, Kanemaru M, Okuyama S et al (2013) Anti-allergic effects of enzymatically modified isoquercitrin (α-oligoglucosyl quercetin 3-O-glucoside), quercetin 3-O-glucoside, α-oligoglucosyl rutin, and quercetin, when administered orally to mice. J Nat Med 67:881–886PubMedGoogle Scholar
  119. Marquez B, Van Bambeke F (2011) ABC multidrug transporters: target for modulation of drug pharmacokinetics and drug–drug interactions. Curr Drug Targets 12:600–620PubMedGoogle Scholar
  120. Matheny CJ, Lamb MW, Brouwer KR, Pollack GM (2001) Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 21:778–796PubMedGoogle Scholar
  121. Matsui T, Ito C, Itoigawa M et al (2009) Effect of natsudaidain isolated from Citrus plants on TNF-alpha and cyclooxygenase-2 expression in RBL-2H3 cells. J Pharm Pharmacol 61:109–114PubMedGoogle Scholar
  122. Mertens-Talcott SU, De Castro WV, Manthey JA et al (2007) Polymethoxylated flavones and other phenolic derivates from citrus in their inhibitory effects on P-glycoprotein-mediated transport of talinolol in Caco-2 cells. J Agric Food Chem 55:2563–2568PubMedGoogle Scholar
  123. Miller DS, Bauer B, Hart AMS (2009) Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve CNS pharmacotherapy. Pharmacol Rev 60:196–209Google Scholar
  124. Mitsunaga Y, Takanaga H, Matsuo H et al (2000) Effect of bioflavonoids on vincristine transport across blood–brain barrier. Eur J Pharmacol 395:193–201PubMedGoogle Scholar
  125. Miyake Y, Mochizuki M, Okada M et al (2007) Isolation of antioxidative phenolic glucosides from lemon juice and their suppressive effect on the expression of blood adhesion molecules. Biosci Biotechnol Biochem 71:1911–1919PubMedGoogle Scholar
  126. Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y (2003) Impact of drug transporter studies on drug discovery and development. Pharmacol Rev 55:425–461PubMedGoogle Scholar
  127. Moon YJ, Wang X, Morris ME (2006) Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Toxicol Vitr 20:187–210Google Scholar
  128. Moreno Escobosa MC, Cruz Granados S, Moya Quesada MC (2012) Erythema and hand edema due to flavoxate. J Investig Allergol Clin Immunol 22:390–391PubMedGoogle Scholar
  129. Morris ME, Zhang S (2006) Flavonoid-drug interactions: effects of flavonoids on ABC transporters. Life Sci 78:2116–2130PubMedGoogle Scholar
  130. Ofer M, Wolffram S, Koggel A et al (2005) Modulation of drug transport by selected flavonoids: involvement of P-gp and OCT? Eur J Pharm Sci 25:263–271PubMedGoogle Scholar
  131. Ogawa Y, Oku H, Iwaoka E et al (2006) Allergy-preventive phenolic glycosides from Populus sieboldii. J Nat Prod 69:1215–1217PubMedGoogle Scholar
  132. Palmeira A, Rodrigues F, Sousa E et al (2011) New uses for old drugs: pharmacophore-based screening for the discovery of P-glycoprotein inhibitors. Chem Biol Drug Des 78:57–72PubMedGoogle Scholar
  133. Park JH, Park JH, Hur HJ et al (2012) Effects of silymarin and formulation on the oral bioavailability of paclitaxel in rats. Eur J Pharm Sci 45:296–301PubMedGoogle Scholar
  134. Patanasethanont D, Nagai J, Yumoto R et al (2007) Effects of Kaempferia Parviflora extracts and their flavone constituents on P-glycoprotein function. J Pharm Sci 96:223–233Google Scholar
  135. Pathak SM, Udupa N (2010) Pre-clinical evidence of enhanced oral bioavailability of the P-glycoprotein substrate talinolol in combination with morin. Biopharm Drug Dispos 31:202–214PubMedGoogle Scholar
  136. Peng SX, Ritchie DM, Cousineau M et al (2006) Altered oral bioavailability and pharmacokinetics of P-glycoprotein substrates by coadministration of biochanin A. J Pharm Sci 95:1984–1993PubMedGoogle Scholar
  137. Pérez-Tomás R (2006) Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr Med Chem 13:1859–1876PubMedGoogle Scholar
  138. Piao Y-J, Choi J-S (2008a) Effects of morin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine in rats. J Pharm Pharmacol 60:625–629PubMedGoogle Scholar
  139. Piao Y-J, Choi J-S (2008b) Enhanced bioavailability of verapamil after oral administration with hesperidin in rats. Arch Pharm Res 31:518–522PubMedGoogle Scholar
  140. Piao Y-J, Shin S-C, Choi J-S (2008) Effects of oral kaempferol on the pharmacokinetics of tamoxifen and one of its metabolites, 4-hydroxytamoxifen, after oral administration of tamoxifen to rats. Biopharm Drug Dispos 29:245–249PubMedGoogle Scholar
  141. Potschka H (2012) Role of CNS efflux drug transporters in antiepileptic drug delivery: overcoming CNS efflux drug transport. Adv Drug Deliv Rev 64:943–952PubMedGoogle Scholar
  142. PubChem Coumpound Database PubChem Coumpound Database.
  143. Raj (2001) Bioflavonoids classification, pharmacological, biochemical effects and therapeutic potential. Indian J Pharmacol 33:2Google Scholar
  144. Rakwal R, Agrawal G, Yonekura M, Kodama O (2000) Naringenin 7-O-methyltransferase involved in the biosynthesis of the flavanone phytoalexin sakuranetin from rice (Oryza sativa L.). Plant Sci 155:213–221PubMedGoogle Scholar
  145. Ramakrishnan P (2003) The role of P-glycoprotein in the blood–brain barrier. Einstein J Biol Med 19:160–165Google Scholar
  146. Rao BN, Srinivas M, Kumar YS, Rao YM (2007) Effect of silymarin on the oral bioavailability of ranitidine in healthy human volunteers. Drug Metab Drug Interact 22:175–185Google Scholar
  147. Rao YK, Lee M-J, Chen K et al (2011) Insulin-mimetic action of rhoifolin and cosmosiin isolated from Citrus grandis (L.) Osbeck leaves: enhanced adiponectin secretion and insulin receptor phosphorylation in 3T3-L1 Cells. Evid Based Complement Alternat Med 2011:624375 Google Scholar
  148. Raub TJ (2006) P-glycoprotein recognition of substrates and circumvention through rational drug design. Mol Pharm 3:3–25PubMedGoogle Scholar
  149. Romano B, Pagano E, Montanaro V et al (2013) Novel Insights into the pharmacology of flavonoids. Phytother Res 27:1588–1596PubMedGoogle Scholar
  150. Romiti N, Tramonti G, Donati A, Chieli E (2004) Effects of grapefruit juice on the multidrug transporter P-glycoprotein in the human proximal tubular cell line HK-2. Life Sci 76:293–302PubMedGoogle Scholar
  151. Ross JA, Kasum CM (2002) Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 22:19–34PubMedGoogle Scholar
  152. Sacco S, Maffei M (1997) The effect of isosakuranetin (5,7-dihydroxy 4′-methoxy flavanone) on potassium uptake in wheat root segments. Phytochemistry 46:245–248Google Scholar
  153. Sauna ZE, Smith MM, Marianna M, Kerr KM (2001) The mechanism of action of multidrug-resistance-linked P-glycoprotein. J Bioenerg Biomembr 33:481–491Google Scholar
  154. Scambia G, Ranelletti FO, Panici PB et al (1994) Quercetin potentiates the effect of Adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target. Cancer Chemother Pharmacol 34:459–464PubMedGoogle Scholar
  155. Schinkel A (1999) P-Glycoprotein, a gatekeeper in the blood–brain barrier. Adv Drug Deliv Rev 36:179–194PubMedGoogle Scholar
  156. Schinkel AH, Jonker JW (2012) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 55:3–29Google Scholar
  157. Seegers U, Potschka H, Löscher W (2002) Lack of effects of prolonged treatment with phenobarbital or phenytoin on the expression of P-glycoprotein in various rat brain regions. Eur J Pharmacol 451:149–155PubMedGoogle Scholar
  158. Shajib MTI, Pedersen HA, Mortensen AG et al (2012) Phytotoxic effect, uptake, and transformation of biochanin A in selected weed species. J Agric Food Chem 60:10715–10722PubMedGoogle Scholar
  159. Sheu M-T, Liou Y-B, Kao Y-H et al (2010) A quantitative structure-activity relationship for the modulation effects of flavonoids on p-glycoprotein-mediated transport. Chem Pharm Bull (Tokyo) 58:1187–1194Google Scholar
  160. Shin S-C, Choi J-S, Li X (2006) Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. Int J Pharm 313:144–149PubMedGoogle Scholar
  161. Shin S-C, Piao Y-J, Choi J-S (2008) Effects of morin on the bioavailability of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats. In Vivo (Brooklyn) 22:391–395Google Scholar
  162. Shin SC, Li C, Choi JS (2009) Effects of baicalein, an antioxidant, on the bioavailability of doxorubicin in rats: possible role of P-glycoprotein inhibition by baicalein. Pharmazie 64:579–583PubMedGoogle Scholar
  163. Shohai T, Shafique M, Dhanya N, Divakar MC (2011) Importance of flavonoides in therapeutics. Hygeia J D Med 3:1–18Google Scholar
  164. Singh SP, Wahajuddin Raju KSR et al (2012) Reduced bioavailability of tamoxifen and its metabolite 4-hydroxytamoxifen after oral administration with biochanin A (an isoflavone) in rats. Phytother Res 26:303–307PubMedGoogle Scholar
  165. Spencer JPE (2007) The interactions of flavonoids within neuronal signalling pathways. Genes Nutr 2:257–273PubMedCentralPubMedGoogle Scholar
  166. Stouch TR, Gudmundsson O (2002) Progress in understanding the structure-activity relationships of P-glycoprotein. Adv Drug Deliv Rev 54:315–328Google Scholar
  167. Sugimoto H, Hirabayashi H, Kimura Y et al (2011) Quantitative investigation of the impact of P-glycoprotein inhibition on drug transport across blood–brain barrier in rats. Drug Metab Dispos 39:8–14PubMedGoogle Scholar
  168. Sun H, Dai H, Shaik N, Elmquist WF (2003) Drug efflux transporters in the CNS. Adv Drug Deliv Rev 55:83–105PubMedGoogle Scholar
  169. Sun J, He Z-G, Cheng G et al (2004) Multidrug resistance P-glycoprotein: crucial significance in drug disposition and interaction. Med Sci Monit 10:5–14Google Scholar
  170. 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 21:1062–1066Google Scholar
  171. Takanaga H, Ohnishi A, Yamada S et al (2000) Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cythocrome P450 3A4. J Pharmacol Exp Ther 293:230–236Google Scholar
  172. Tandon VR, Kapoor B, Bano G et al (2006) P-glycoprotein : pharmacological relevance relevance. Indian J Pharmacol 38:13–24Google Scholar
  173. Tapas AR, Sakarkar DM, Kakde RB (2008) Flavonoids as nutraceuticals : a Review. Trop J Pharm Res 7:1089–1099Google Scholar
  174. Thilakarathna SH, Rupasinghe HPV (2013) Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 5:3367–3387PubMedCentralPubMedGoogle Scholar
  175. Thomas H, Coley HM (2013) Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 10:159–165Google Scholar
  176. Toh JY, Tan VMH, Lim PCY et al (2013) Flavonoids from fruit and vegetables: a focus on cardiovascular risk factors. Curr Atheroscler Rep 15:368PubMedGoogle Scholar
  177. Toki K, Saito N, Irie Y et al (2008) 7-O-Methylated anthocyanidin glycosides from Catharanthus roseus. Phytochemistry 69:1215–1219PubMedGoogle Scholar
  178. Tran VH, Marks D, Duke RK et al (2011) Modulation of P-glycoprotein-mediated anticancer drug accumulation, cytotoxicity, and ATPase activity by flavonoid interactions. Nutr Cancer 63:435–443PubMedGoogle Scholar
  179. Trompier D, Baubichon-Cortay H, Chang X-B et al (2003) Multiple flavonoid-binding sites within multidrug resistance protein MRP1. Cell Mol Life Sci 60:2164–2177PubMedGoogle Scholar
  180. Tsuji PA, Stephenson KK, Wade KL et al (2013) Structure-activity analysis of flavonoids: direct and indirect antioxidant, and antiinflammatory potencies and toxicities. Nutr Cancer 65:1014–1025PubMedGoogle Scholar
  181. Udaya Kumar N, Sailendra M, Peddanna K et al (2011) Virtual screening of flavonoids as inhibitory agents of p-glycoprotein. IJABPT 2:130–140Google Scholar
  182. Van der Kolk DM, de Vries EG, van Putten WJ et al (2000) P-glycoprotein and multidrug resistance protein activities in relation to treatment outcome in acute myeloid leukemia. Clin Cancer Res 6:3205–3214PubMedGoogle Scholar
  183. Varma M (2003) P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol Res 48:347–359PubMedGoogle Scholar
  184. Vauzour D, Vafeiadou K, Rodriguez-Mateos A et al (2008) The neuroprotective potential of flavonoids: a multiplicity of effects. Genes Nutr 3:115–126PubMedCentralPubMedGoogle Scholar
  185. Volk H, Burkhardt K, Potschka H et al (2004) Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures. Neuroscience 123:751–759PubMedGoogle Scholar
  186. Wagner H, Aurnhammer G, Hörhammer L et al (1969) Synthesis of poncirin, an isosakuranetin-7-beta-neohesperidoside from Poncirus trifoliata Raf. Chem Ber 102:785–791PubMedGoogle Scholar
  187. Wang EJ, Casciano CN, Clement RP, Johnson WW (2001) Inhibition of P-glycoprotein transport function by grapefruit juice psoralen. Pharm Res 18:432–438Google Scholar
  188. Wang E, Barecki-Roach M, Johnson WW (2002) Elevation of P-glycoprotein function by a catechin in green tea. Biochem Biophys Res Commun 297:412–418PubMedGoogle Scholar
  189. Wang Y-H, Chao P-DL, Hsiu S-L et al (2004) Lethal quercetin-digoxin interaction in pigs. Life Sci 74:1191–1197Google Scholar
  190. Wang Y-H, Li Y, Yang S-L, Yang L (2005) An in silico approach for screening flavonoids as P-glycoprotein inhibitors based on a Bayesian-regularized neural network. J Comput Aided Mol Des 19:137–147PubMedGoogle Scholar
  191. Wang H, Zhao X, Wang Y, Yin S (2007) Potential toxicities of flavonoids. Wei Sheng Yan Jiu 36:640–642PubMedGoogle Scholar
  192. Wasowski C, Marder M (2012) Flavonoids as GABA A receptor ligands: the whole story? J Exp Pharmacol 4:9–24Google Scholar
  193. Wesołowska O (2011) Interaction of phenothiazines, stilbenes and flavonoids with multidrug resistance-associated transporters, P-glycoprotein and MRP1. Acta Biochim Pol 58:433–448PubMedGoogle Scholar
  194. Wesołowska O, Hendrich AB, Łaniapietrzak B et al (2009) Perturbation of the lipid phase of a membrane is not involved in the modulation of MRP1 transport activity by flavonoids. Cell Mol Biol Lett 14:199–221PubMedGoogle Scholar
  195. Yang K, Wu J, Li X (2008) Recent advances in the research of P-glycoprotein inhibitors. Biosci Trends 2:137–146PubMedGoogle Scholar
  196. Yang SH, Lee JH, Lee DY et al (2011) Effects of morin on the pharmacokinetics of docetaxel in rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Arch Pharm Res 34:1729–1734Google Scholar
  197. Yang J, Qian D, Guo J et al (2013) Identification of the major metabolites of hyperoside produced by the human intestinal bacteria using ultra performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. J Ethnopharmacol 147:174–179PubMedGoogle Scholar
  198. Yeum C-H, Choi J-S (2006) Effect of naringin pretreatment on bioavailability of verapamil in rabbits. Arch Pharm Res 29:102–107PubMedGoogle Scholar
  199. Yoo HH, Lee M, Chung HJ et al (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 55:7620–7625PubMedGoogle Scholar
  200. Zhang S, Morris ME (2003a) Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-Glycoprotein-mediated transport. J Pharmacol Exp Ther 304:1258–1267PubMedGoogle Scholar
  201. Zhang S, Morris ME (2003b) Effect of the flavonoids biochanin A and silymarin on the P-glycoprotein-mediated transport of digoxin and vinblastine in human intestinal Caco-2 cells. Pharm Res 20:1184–1191PubMedGoogle Scholar
  202. Zhang L, Strong JM, Qiu W et al (2006) Scientific perspectives on drug transporters and their role in drug interactions. Mol Pharm 3:62–69PubMedGoogle Scholar
  203. Zhang J, Yang G, Lin R, Hu Z (2011) Determination of paeoniflorin, calycosin-7-O-β-D-glucoside, ononin, calycosin and formononetin in rat plasma after oral administration of Buyang Huanwu decoction for their pharmacokinetic study by liquid chromatography-mass spectrometry. Biomed Chromatogr 25:450–457PubMedGoogle Scholar
  204. Zhang C, Kwan P, Zuo Z, Baum L (2012) The transport of antiepileptic drugs by P-glycoprotein. Adv Drug Deliv Rev 64:930–942PubMedGoogle Scholar
  205. Zhou G-X, Lu C-L, Wang H-S, Yao X-S (2009) An acetyl flavonol from Nervilia fordii (Hance) Schltr. J Asian Nat Prod Res 11:498–502PubMedGoogle Scholar
  206. Zhu L, Zhao L, Wang H et al (2013) Oroxylin A reverses P-glycoprotein-mediated multidrug resistance of MCF7/ADR cells by G2/M arrest. Toxicol Lett 219:107–115Google Scholar
  207. Zou P, Xing L, Tang Q et al (2012) Comparative evaluation of the teratogenicity of genistein and genistin using rat whole embryo culture and limbud micromass culture methods. Food Chem Toxicol 50:2831–2836PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Ana Ferreira
    • 1
    • 2
  • Sarah Pousinho
    • 1
  • Ana Fortuna
    • 2
    • 3
  • Amílcar Falcão
    • 2
    • 3
  • Gilberto Alves
    • 1
    • 2
  1. 1.CICS-UBI – Health Sciences Research CentreUniversity of Beira InteriorCovilhãPortugal
  2. 2.CNC – Centre for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal
  3. 3.Laboratory of Pharmacology, Faculty of PharmacyUniversity of CoimbraCoimbraPortugal

Personalised recommendations