Vitamin E-Drug Interactions

Part of the Nutrition and Health book series (NH)


Dietary vitamin E supplements, often containing high doses of vitamin E, are frequently consumed by people treated with one or more prescription drugs. Interactions of vitamin E with drugs therefore need to be considered. In this chapter, we introduce the basics of nutrient-drug interactions: interactions affecting the pharmacokinetics (the metabolism of a drug) or pharmacodynamics (the effect of a drug) of drugs. We then review the evidence in the scientific literature to assess the potential of all eight vitamin E congeners to interact with drugs. In summary, there is no evidence for vitamin E-drug interactions at vitamin E intakes achievable by diet. High-dose (≥300 mg/d) supplementation of vitamin E, especially of α-tocopherol, however, may lead to interactions with aspirin, warfarin, tamoxifen, and cyclosporine A. For the majority of drugs, interactions with vitamin E, even at high doses, have not been observed and are unlikely to occur.


Nutrient-drug interactions Tocopherols Tocotrienols Pharmacokinetics Pharmacodynamics 


  1. 1.
    Kantor ED, Rehm CD, Du M, White E, et al. Trends in dietary supplement use among US adults from 1999–2012. JAMA. 2016;316:1464.CrossRefGoogle Scholar
  2. 2.
    Max Rubner-Institut. Nationale Verzehrsstudie II: Ergebnisbericht Teil 2. Karlsruhe; 2008.Google Scholar
  3. 3.
    Institute of Medicine. Dietary reference intakes for vitamin C, vitamin E, selenium and carotenoids. Washington, DC: National Academy Press; 2000. p. 186–283.Google Scholar
  4. 4.
    Wolfram G. New reference values for nutrient intake in Germany, Austria and Switzerland (DACH-reference values). Forum Nutr. 2003;56:95–7.PubMedGoogle Scholar
  5. 5.
    Kupferschmidt HH, Ha HR, Ziegler WH, Meier PJ, et al. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther. 1995;58:20–8.CrossRefGoogle Scholar
  6. 6.
    Dürr D, Stieger B, Kullak-Ublick GA, Rentsch KM, et al. St John’s Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther. 2000;68:598–604.CrossRefGoogle Scholar
  7. 7.
    Fasco MJ, Principe LM. R- and S-warfarin inhibition of vitamin K and vitamin K 2,3-epoxide reductase activities in the rat. J Biol Chem. 1982;257:4894–901.PubMedGoogle Scholar
  8. 8.
    Lurie Y, Loebstein R, Kurnik D, Almog S, et al. Warfarin and vitamin K intake in the era of pharmacogenetics. Br J Clin Pharmacol. 2010;70:164–70.CrossRefGoogle Scholar
  9. 9.
    Gonzalez FJ, Nebert DW. Evolution of the P450 gene superfamily: animal-plant “warfare”, molecular drive and human genetic differences in drug oxidation. Trends Genet. 1990;6:182–6.CrossRefGoogle Scholar
  10. 10.
    Williams RT. Detoxication mechanisms: the metabolism of drugs and allied organic compounds. London: Chapman & Hall Ltd; 1947.Google Scholar
  11. 11.
    Ishikawa T. The ATP-dependent glutathione S-conjugate export pump. Trends Biochem Sci. 1992;17:463–8.CrossRefGoogle Scholar
  12. 12.
    Josephy DP, Guengerich PF, Miners JO. “Phase I and phase II” drug metabolism: terminology that we should phase out? Drug Metab Rev. 2005;37:575–80.CrossRefGoogle Scholar
  13. 13.
    Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci. 1987;84:7735–8.CrossRefGoogle Scholar
  14. 14.
    Mayer U, Wagenaar E, Beijnen JH, Smit JW, et al. Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr 1a P-glycoprotein. Br J Pharmacol. 1996;119:1038–44.CrossRefGoogle Scholar
  15. 15.
    Silva R, Vilas-Boas V, Carmo H, Dinis-Oliveira RJ, et al. Modulation of P-glycoprotein efflux pump: induction and activation as a therapeutic strategy. Pharmacol Ther. 2015;149:1–123.CrossRefGoogle Scholar
  16. 16.
    Zhou C, Tabb MM, Sadatrafiei A, Grün F, et al. Tocotrienols activate the steroid and xenobiotic receptor, SXR, and selectively regulate expression of its target genes. Drug Metab Dispos. 2004;32:1075–82.CrossRefGoogle Scholar
  17. 17.
    Podszun MC, Jakobi M, Birringer M, Weiss J, et al. The long chain α–tocopherol metabolite α-13’-COOH and γ-tocotrienol induce P-glycoprotein expression and activity by activation of the pregnane X receptor in the intestinal cell line LS 180. Mol Nutr Food Res. 2016;61(3):1–9.Google Scholar
  18. 18.
    Abuznait AH, Qosa H, O’Connell ND, Akbarian-Tefaghi J, et al. Induction of expression and functional activity of P-glycoprotein efflux transporter by bioactive plant natural products. Food Chem Toxicol. 2011;49:2765–72.CrossRefGoogle Scholar
  19. 19.
    Paine MF, Shen DD, Kunze KL, Perkins JD, et al. First-pass metabolism of midazolam by the human intestine*. Clin Pharmacol Ther. 1996;60:14–24.CrossRefGoogle Scholar
  20. 20.
    Podszun MC, Grebenstein N, Hofmann U, Frank J. High-dose supplementation with natural α-tocopherol does neither alter the pharmacodynamics of atorvastatin nor its phase I metabolism in guinea pigs. Toxicol Appl Pharmacol. 2013;266:452–8.CrossRefGoogle Scholar
  21. 21.
    Wang W, Higuchi CM. Induction of NAD(P)H:quinone reductase by vitamins A, E and C in Colo205 colon cancer cells. Cancer Lett. 1995;98:63–9.PubMedGoogle Scholar
  22. 22.
    Van der Logt EMJ, Roelofs HMJ, van Lieshout EMM, Nagengast FM, et al. Effects of dietary anticarcinogens and nonsteroidal anti-inflammatory drugs on rat gastrointestinal UDP-glucuronosyltransferases. Anticancer Res. 2004;24:843–9.PubMedGoogle Scholar
  23. 23.
    Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158:693–705.CrossRefGoogle Scholar
  24. 24.
    Hsiang B, Zhu Y, Wang Z, Wu Y, et al. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem. 1999;274:37161–8.CrossRefGoogle Scholar
  25. 25.
    Hagenbuch B, Meier P. The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta Biomembr. 2003;1609:1–18.CrossRefGoogle Scholar
  26. 26.
    König J, Cui Y, Nies AT, Keppler D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol. 2000;278:G156–64.CrossRefGoogle Scholar
  27. 27.
    Traber MG, Labut EM, Leonard SW, Lebold KM. α-Tocopherol injections in rats up-regulate hepatic ABC transporters, but not cytochrome P450 enzymes. Free Radic Biol Med. 2011;51:2031–40.CrossRefGoogle Scholar
  28. 28.
    Farley SM, Leonard SW, Labut EM, Raines HF, et al. Vitamin E decreases extra-hepatic menaquinone-4 concentrations in rats fed menadione or phylloquinone. Mol Nutr Food Res. 2012;56:912–22.CrossRefGoogle Scholar
  29. 29.
    Sontag TJ, Parker RS. Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. J Biol Chem. 2002;277:25290–6.CrossRefGoogle Scholar
  30. 30.
    Bardowell SA, Ding X, Parker RS. Disruption of P450-mediated vitamin E hydroxylase activities alters vitamin E status in tocopherol supplemented mice and reveals extra-hepatic vitamin E metabolism. J Lipid Res. 2012;53:2667–76.CrossRefGoogle Scholar
  31. 31.
    Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol. 1999;39:1–17.CrossRefGoogle Scholar
  32. 32.
    Lehmann JM, McKee DD, Watson MA, Willson TM, et al. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest. 1998;102:1016–23.CrossRefGoogle Scholar
  33. 33.
    Landes N, Pfluger P, Kluth D, Birringer M, et al. Vitamin E activates gene expression via the pregnane X receptor. Biochem Pharmacol. 2003;65:269–73.CrossRefGoogle Scholar
  34. 34.
    Hundhausen C, Frank J, Rimbach G, Stoecklin E, et al. Effect of vitamin E on cytochrome P450 mRNA levels in cultured hepatocytes (HepG2) and in rat liver. Animals. 2006;190:183–90.Google Scholar
  35. 35.
    Kluth D, Landes N, Pfluger P, Müller-Schmehl K, et al. Modulation of Cyp3a11 mRNA expression by alpha-tocopherol but not gamma-tocotrienol in mice. Free Radic Biol Med. 2005;38:507–14.CrossRefGoogle Scholar
  36. 36.
    Mustacich DJ, Gohil K, Bruno RS, Yan M, et al. Alpha-tocopherol modulates genes involved in hepatic xenobiotic pathways in mice. J Nutr Biochem. 2009;20:469–76.CrossRefGoogle Scholar
  37. 37.
    Leonard SW, Joss JD, Mustacich DJ, Blatt DH, et al. Effects of vitamin E on cholesterol levels of hypercholesterolemic patients receiving statins. Am J Health Syst Pharm. 2007;64:2257–66.CrossRefGoogle Scholar
  38. 38.
    Mandrioli R, Mercolini L, Raggi MA. Benzodiazepine metabolism: an analytical perspective. Curr Drug Metab. 2008;9:827–44.CrossRefGoogle Scholar
  39. 39.
    Clarke MW, Burnett JR, Wu JHY, Hodgson JM, et al. Vitamin E supplementation and hepatic drug metabolism in humans. J Cardiovasc Pharmacol. 2009;54:491–6.CrossRefGoogle Scholar
  40. 40.
    Manson MM, Ball HW, Barrett MC, Clark HL, et al. Mechanism of action of dietary chemoprotective agents in rat liver: induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism. Carcinogenesis. 1997;18:1729–38.CrossRefGoogle Scholar
  41. 41.
    Mustacich DJ, Shields J, Horton RA, Brown MK, et al. Biliary secretion of a -tocopherol and the role of the mdr2 P-glycoprotein in rats and mice 1. Arch Biochem Biophys. 2011;350:183–92.CrossRefGoogle Scholar
  42. 42.
    Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV, et al. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Proje. J Clin Oncol. 1990;8:1005–18.CrossRefGoogle Scholar
  43. 43.
    Shou J, Massarweh S, Osborne CK, Wakeling AE, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96:926–35.CrossRefGoogle Scholar
  44. 44.
    Peralta EA, Viegas ML, Louis S, Engle DL, et al. Effect of vitamin E on tamoxifen-treated breast cancer cells. Surgery. 2006;140:607-14–5.CrossRefGoogle Scholar
  45. 45.
    Chamras H, Barsky SH, Ardashian A, Navasartian D, et al. Novel interactions of vitamin E and estrogen in breast cancer. Nutr Cancer. 2005;52:43–8.CrossRefGoogle Scholar
  46. 46.
    Peralta EA, Brewer AT, Louis S, Dunnington GL. Vitamin E increases biomarkers of estrogen stimulation when taken with tamoxifen. J Surg Res. 2009;153:143–7.CrossRefGoogle Scholar
  47. 47.
    Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004;310:1062–75.CrossRefGoogle Scholar
  48. 48.
    Baliga R, Ueda N, Walker PD, Shah SV. Oxidant mechanisms in toxic acute renal failure. Drug Metab Rev. 1999;31:971–97.CrossRefGoogle Scholar
  49. 49.
    Blackhall ML, Fassett RG, Sharman JE, Geraghty DP, et al. Effects of antioxidant supplementation on blood cyclosporin A and glomerular filtration rate in renal transplant recipients. Nephrol Dial Transplant. 2005;20:1970–5.CrossRefGoogle Scholar
  50. 50.
    de Vries APJ, Oterdoom LH, Gans ROB, Bakker SJL. Supplementation with anti-oxidants vitamin C and E decreases cyclosporine A trough-levels in renal transplant recipients. Nephrol Dial Transplant. 2006;21:231–2.CrossRefGoogle Scholar
  51. 51.
    Lake KD, Aaronson KD, Gorman LE, Pagani FD, et al. Effect of oral vitamin E and C therapy on calcineurin inhibitor levels in heart transplant recipients. J Heart Lung Transplant. 2005;24:990–4.CrossRefGoogle Scholar
  52. 52.
    Barany P, Stenvinkel P, Ottosson-Seeberger A, Alvestrand A, et al. Effect of 6 weeks of vitamin E administration on renal haemodynamic alterations following a single dose of neoral in healthy volunteers. Nephrol Dial Transpl. 2001;16:580–4.CrossRefGoogle Scholar
  53. 53.
    de Jonge H, de Loor H, Verbeke K, Vanrenterghem Y, et al. In vivo CYP3A4 activity, CYP3A5 genotype, and hematocrit predict tacrolimus dose requirements and clearance in renal transplant patients. Clin Pharmacol Ther. 2012;92:366–75.CrossRefGoogle Scholar
  54. 54.
    OSTERUD B, BJORKLID E. Role of monocytes in Atherogenesis. Physiol Rev. 2003;83:1069–112.CrossRefGoogle Scholar
  55. 55.
    Reiter R, Resch U, Sinzinger H. Do human platelets express COX-2? Prostaglandins Leukot Essent Fatty Acids. 2001;64:299–305.CrossRefGoogle Scholar
  56. 56.
    Roth G, Majerus PW. The mechanism of the effect of aspirin. Acetylation of a particulate fraction protein. J Clin Invest. 1975;56:624–32.CrossRefGoogle Scholar
  57. 57.
    Ali M, Gudbranson C, McDonald J. Inhibition of human platelet cyclooxygenase by alpha-tocopherol. Prostaglandins Med. 1980;4:79–85.CrossRefGoogle Scholar
  58. 58.
    Freedman JE, Keaney JF. Vitamin E inhibition of platelet aggregation is independent of antioxidant activity. J Nutr. 2001;131:374S–7S.CrossRefGoogle Scholar
  59. 59.
    Freedman JE, Farhat JH, Loscalzo J, Keaney JF. alpha-tocopherol inhibits aggregation of human platelets by a protein kinase C-dependent mechanism. Circulation. 1996;94:2434–40.CrossRefGoogle Scholar
  60. 60.
    Boscoboinik D, Szewczyk A, Henseys C, Ami A. Inhibition of cell proliferation by α-tocopherol. J Biol Chem. 1991;266:6188–94.PubMedGoogle Scholar
  61. 61.
    Azzi A, Boscoboinik D, Clément S, Marilley D, et al. Alpha-tocopherol as a modulator of smooth muscle cell proliferation. Prostaglandins Leukot Essent Fatty Acids. 1997;57:507–14.CrossRefGoogle Scholar
  62. 62.
    Ricciarelli R, Tasinato A, Clément S, Ozer NK, et al. alpha-Tocopherol specifically inactivates cellular protein kinase C alpha by changing its phosphorylation state. Biochem J. 1998;334(Pt 1):243–9.CrossRefGoogle Scholar
  63. 63.
    Steiner M. Effect of alpha-tocopherol administration on platelet function in man. Thromb Haemost. 1983;49:73–7.PubMedGoogle Scholar
  64. 64.
    Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res. 2003;110:255–8.CrossRefGoogle Scholar
  65. 65.
    Liede K, Haukka J. Increased tendency towards gingival bleeding caused by joint effect of α-tocopherol supplementation and acetylsalicylic acid. Ann Med. 1998;30:542–6.CrossRefGoogle Scholar
  66. 66.
    Steiner M, Glantz M, Lekos A. Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks. Am J Clin Nutr. 1995;62:1381S–4S.CrossRefGoogle Scholar
  67. 67.
    Shiotani A, Kamada T, Haruma K. Low-dose aspirin-induced gastrointestinal diseases: past, present, and future. J Gastroenterol. 2008;43:581–8.CrossRefGoogle Scholar
  68. 68.
    Sontag TJ, Parker RS. Cytochrome P450 -hydroxylase pathway of tocopherol catabolism. Biochemistry. 2002;277:25290–6.Google Scholar
  69. 69.
    Bardowell SA, Duan F, Manor D, Swanson JE, et al. Disruption of mouse cytochrome p450 4f14 (Cyp4f14 gene) causes severe perturbations in vitamin E metabolism. J Biol Chem. 2012;287:26077–86.CrossRefGoogle Scholar
  70. 70.
    Edson KZ, Prasad B, Unadkat JD, Suhara Y, et al. Cytochrome P450-dependent catabolism of vitamin K: ω-hydroxylation catalyzed by human CYP4F2 and CYP4F11. Biochemistry. 2013;52:8276–85.CrossRefGoogle Scholar
  71. 71.
    Hirsh J, Dalen JE, Anderson DR, Poller L, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119:8–21.CrossRefGoogle Scholar
  72. 72.
    Corrigan J. Effect of vitamin warfarin-induced E on prothrombin levels vitamin K deficiency. Am J Clin Nutr. 1981;34:1701–5.CrossRefGoogle Scholar
  73. 73.
    Kim JM, White RH. Effect of vitamin E on the anticoagulant response to warfarin. Am J Cardiol. 1996;77:545–6.CrossRefGoogle Scholar
  74. 74.
    Vacca JP, Condra JH. Clinically effective HIV-1 protease inhibitors. Drug Discov Today. 1997;2:261–72.CrossRefGoogle Scholar
  75. 75.
    Dressman J, Kincer J, Matveev SV, Guo L, et al. HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages. J Clin Invest. 2003;111:389–97.CrossRefGoogle Scholar
  76. 76.
    Collot-Teixeira S, De Lorenzo F, Waters L, Fletcher C, et al. Impact of different low-dose ritonavir regimens on lipids, CD36, and adipophilin expression. Clin Pharmacol Ther. 2009;85:375–8.CrossRefGoogle Scholar
  77. 77.
    Stein JH, Klein MA, Bellehumeur JL, McBride PE, et al. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation. 2001;104:257–62.CrossRefGoogle Scholar
  78. 78.
    Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013;13:709–21.CrossRefGoogle Scholar
  79. 79.
    Munteanu A, Zingg J-M, Ricciarelli R, Azzi A. CD36 overexpression in ritonavir-treated THP-1 cells is reversed by alpha-tocopherol. Free Radic Biol Med. 2005;38:1047–56.CrossRefGoogle Scholar
  80. 80.
    Barella L, Muller PY, Schlachter M, Hunziker W, et al. Identification of hepatic molecular mechanisms of action of α-tocopherol using global gene expression profile analysis in rats. Biochim Biophys Acta. 2004;1689:66–74.CrossRefGoogle Scholar
  81. 81.
    Gaedicke S, Zhang X, Schmelzer C, Lou Y, et al. Vitamin E dependent microRNA regulation in rat liver. FEBS Lett. 2008;582:3542–6.CrossRefGoogle Scholar
  82. 82.
    Podszun MC, Grebenstein N, Spruss A, Schlueter T, et al. Dietary α-tocopherol and atorvastatin reduce high-fat-induced lipid accumulation and down-regulate CD36 protein in the liver of guinea pigs. J Nutr Biochem. 2014;25:573–9.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Institute of Nutritional SciencesUniversity of HohenheimStuttgartGermany

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