Clinical Pharmacokinetics

, Volume 42, Issue 5, pp 437–459

Clinical Pharmacokinetics of Antioxidants and Their Impact on Systemic Oxidative Stress

  • Edzard Schwedhelm
  • Renke Maas
  • Raphael Troost
  • Rainer H. Böger
Review Article

Abstract

Dietary antioxidants play a major role in maintaining the homeostasis of the oxidative balance. They are believed to protect humans from disease and aging. Vitamin C (ascorbic acid), vitamin E (tocopherol), β-carotene and other micronutrients such as carotenoids, polyphenols and selenium have been evaluated as antioxidant constituents in the human diet. This article addresses data provided from clinical trials, highlighting the clinical pharmacokinetics of vitamin C, vitamin E, β-carotene, lycopene, lutein, quercetin, rutin, catechins and selenium.

The bioavailability of vitamin C is dose-dependent. Saturation of transport occurs with dosages of 200–400) mg/day. Vitamin C is not protein-bound and is eliminated with an elimination half-life (t½) of 10 hours. In Western populations plasma vitamin C concentrations range from 54–91 µmol/L. Serum α- and γ-tocopherol range from 21 µmol/L (North America) to 27 µmol/L (Europe) and from 3.1 µmol/L to 1.5 µmol/L, respectively. α-Tocopherol is the most abundant tocopherol in human tissue. The bioavailability of all-rac-α-tocopherol is estimated to be 50% of R,R,R-α-tocopherol. The hepatic α-tocopherol transfer protein (α-TTP) together with the tocopherol-associated proteins (TAP) are responsbile for the endogenous accumulation of natural α-tocopherol. Elimination of α-tocopherol takes several days with a t½ of 81 and 73 hours for R,R,R-α-tocopherol and all-rac-α-tocopherol, respectively. The t½ of tocotrienols is short, ranging from 3.8–4.4 hours for γ- and α-tocotrienol, respectively. γ-Tocopherol is degraded to 2, 7, 8-trimethyl-2-(β-carboxyl)-6-hyrdoxychroman by the liver prior to renal elimination. Blood serum carotenoids in Western populations range from 0.28–0.52 p,mol/L for β-carotene, from 0.2–0.28 for lutein, and from 0.29–0.60 for lycopene. All-trans-carotenoids have a better bioavailability than the 9-cis-forms. Elimination of carotenoids takes several days with a t½ of 5-7 and 2–3 days for β-carotene and lycopene, respectively. The bioconversion of β-carotene to retinal is dose-dependent, and ranges between 27% and 2% for a 6 and 126mg dose, respectively. Several oxidised metabolites of carotenoids are known. Flavonols such as quercetin glycosides and rutin are predominantly absorbed as aglycones, bound to plasma proteins and subsequently conjugated to glucuronide, sulfate, and methyl moieties. The t½ ranges from 12–19 hours. The bioavailabillity of catechins is low and they are eliminated with a t½ of 2–4 hours. Catechins are degraded to several γ-valerolactone derivatives and phase II conjugates have also been identified. Only limited clinical pharmacokinetic data for other polyphenols such as resveratrol have been reported to date.

References

  1. 1.
    Sies H. Strategies of antioxidant defense. Eur J Biochem 1993; 215: 213–9PubMedCrossRefGoogle Scholar
  2. 2.
    Thérond P, Bonnefont-Rousselot D, Davit-Spraul A, et al. Biomarkers of oxidative stress: an analytical approach. Curr Opin Clin Nutr Metab Care 2000; 3: 373–84PubMedCrossRefGoogle Scholar
  3. 3.
    De Zwart LL, Meerman JHN, Commandeur JNM, et al. Biomarkers of free radical damage: applications in experimental animals and in humans. Free Radic Biol Med 1999; 26: 202–26PubMedCrossRefGoogle Scholar
  4. 4.
    Halliwell B. Establishing the significance and optimal intake of dietary antioxidants: the biomarker concept. Nutr Rev 1999; 57: 104–13PubMedCrossRefGoogle Scholar
  5. 5.
    McCall MR, Frei B. Can antioxidant vitamins materially reduce oxidative damage in humans? Free Radic Biol Med 1999; 26: 1034–53PubMedCrossRefGoogle Scholar
  6. 6.
    Price JE, Fowkes FG. Antioxidant vitamins in the prevention of cardiovascular disease: the epidemiological evidence. Eur Heart J 1997; 18:719–27PubMedCrossRefGoogle Scholar
  7. 7.
    Flagg EW, Coates RJ, Greenberg RS. Epidemiologie studies of antioxidants and cancer in humans. J Am Coll Nutr 1995; 14: 419–27PubMedGoogle Scholar
  8. 8.
    Adams AK, Wermuth EO, McBride PE. Antioxidant vitamins and the prevention of coronary heart disease. Am Fam Physician 1999; 60: 895–904PubMedGoogle Scholar
  9. 9.
    Ascherio A. Antioxidants and stroke. Am J Clin Nutr 2000; 72: 337–8PubMedGoogle Scholar
  10. 10.
    Lee IM. Antioxidant vitamins in the prevention of cancer. Proc Assoc Am Physicians 1999; 111: 10–5PubMedCrossRefGoogle Scholar
  11. 11.
    Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 1999; 69: 1086–107PubMedGoogle Scholar
  12. 12.
    Cooke MS, Evans MD, Podmore ID, et al. Novel repair action of vitamin C upon in vivo oxidative DNA damage. FEBS Lett 1998; 439: 363–7PubMedCrossRefGoogle Scholar
  13. 13.
    Huang HY, Helzlsouer KJ, Appel LJ. The effect of vitamin C and vitamin E on oxidative DNA damage: results from a randomized controlled trial. Cancer Epidemiol Biomarkers Prev 2000; 9: 647–52PubMedGoogle Scholar
  14. 14.
    Porkkala-Sarataho E, Salonen JT, Nyyssönen K, et al. Longterm effects of vitamin E, vitamin C, and combined supplementation on urinary 7-hydro-8-oxo-2′-deoxyguanosine, serum cholesterol oxidation products, and oxidation resistance of lipids in nondepleted men. Arterioscler Thromb Vasc Biol 2000; 20: 2087–93PubMedCrossRefGoogle Scholar
  15. 15.
    Levine M, Wang Y, Padayatty SJ, et al. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci USA 2001; 98: 9842–6PubMedCrossRefGoogle Scholar
  16. 16.
    Brown AA, Hu FB. Dietary modulation of endothelial function: implications for cardiovascular disease. Am J Clin Nutr 2001; 73: 673–86PubMedGoogle Scholar
  17. 17.
    Young VR. Evidence for a recommended dietary allowance for vitamin C from pharmacokinetics: a comment and analysis. Proc Natl Acad Sci U S A 1996; 93: 14344–8PubMedCrossRefGoogle Scholar
  18. 18.
    Mangels AR, Block G, Frey CM, et al. The bioavailability to humans of ascorbic acid from oranges, orange juice and cooked broccoli is similar to that of synthetic ascorbic acid. J Nutr 1993; 123: 1054–61PubMedGoogle Scholar
  19. 19.
    Johnston CS, Luo B. Comparison of the absorption and excretion of three commercially available sources of vitamin C. J Am Diet Assoc 1994; 94: 779–81PubMedCrossRefGoogle Scholar
  20. 20.
    Levine M, Conry-Cantilena C, Wang Y, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A 1996; 93: 3704–9PubMedCrossRefGoogle Scholar
  21. 21.
    Olmedilla B, Granado F, Southon S, et al. Serum concentrations of carotenoids and vitamins A, E, and C in control subjects from five European countries. Br J Nutr 2001; 85: 227–38PubMedCrossRefGoogle Scholar
  22. 22.
    Blanchard J. Depletion and repletion kinetics of vitamin C in humans. J Nutr 1991; 121: 170–6PubMedGoogle Scholar
  23. 23.
    Behrens WA, Madere R. Alpha- and gamma tocopherol concentrations in human serum. J Am Coll Nutr 1986; 5: 91–6PubMedGoogle Scholar
  24. 24.
    Curran-Clementano J, Hammond Jr BR, Ciulla TA. Relation between dietary intake, serum concentrations, and retinal concentrations of lutein and zeaxanthin in adults in a Midwest population. Am J Clin Nutr 2001; 74: 796–802Google Scholar
  25. 25.
    Wang YH, Dhariwal KR, Levine M. Ascorbic acid bioavailability in humans: ascorbic acid in plasma, serum, and urine. Ann N Y Acad Sci 1992; 669: 383–6PubMedCrossRefGoogle Scholar
  26. 26.
    Oreopoulos DG, Lindeman RD, VanderJagt DJ, et al. Renal excretion of ascorbic acid: effect of age and sex. J Am Coll Nutr 1993; 12: 537–42PubMedGoogle Scholar
  27. 27.
    Wasko P, Rotrosen D, Levine M. Ascorbic acid transport and accumulation in human neutrophils. J Biol Chem 1989; 264: 18996–9002Google Scholar
  28. 28.
    Welch RW, Bergsten P, Butler J, et al. Ascorbic acid accumulation and transport in human fibroblasts. Biochem J 1993; 294: 505–10PubMedGoogle Scholar
  29. 29.
    Blanchard J. Depletion and repletion kinetics of vitamin C in humans. J Nutr 1991; 121: 170–6PubMedGoogle Scholar
  30. 30.
    Hellman L, Burns JJ. Metabolism of L-ascorbic acid 1-C14 in man. J Biol Chem 1958; 230: 923–31PubMedGoogle Scholar
  31. 31.
    Hornig D. Metabolism and requirements of ascorbic acid in man. S Afr Med J 1981; 60: 818–23PubMedGoogle Scholar
  32. 32.
    Mendiratta S, Qu ZC, May JM. Erythrocyte ascorbate recycling: antioxidant effects in blood. Free Radic Biol Med 1998; 24: 789–97PubMedCrossRefGoogle Scholar
  33. 33.
    Bode AM. Metabolism of vitamin C. Adv Pharmacol 1997; 38: 21–47PubMedCrossRefGoogle Scholar
  34. 34.
    Ogawa Y, Miyazato T, Hatano T. Oxalate and urinary stones. World J Surg 2000; 24: 1154–9PubMedCrossRefGoogle Scholar
  35. 35.
    Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993; 328: 1450–6PubMedCrossRefGoogle Scholar
  36. 36.
    Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary disease in woman. N Engl J Med 1993; 328: 1444–9PubMedCrossRefGoogle Scholar
  37. 37.
    The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994; 330: 1029–35CrossRefGoogle Scholar
  38. 38.
    Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996; 347: 781–6PubMedCrossRefGoogle Scholar
  39. 39.
    GISSI-Prevention Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevention trial. Lancet 1999; 354: 447–55CrossRefGoogle Scholar
  40. 40.
    The Heart Outcomes Prevention Evaluation Study Investigators. Vitamin E supplementation and cardiovascular events in highrisk patients. N Engl J Med 2000; 342: 154–60CrossRefGoogle Scholar
  41. 41.
    Collaborative Group of the Primary Prevention Project (PPP). Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet 2001; 357: 89–95CrossRefGoogle Scholar
  42. 42.
    Heart Protection Study Collaborative Group. MRC/BHFHeart protection study of antioxidant vitamin supplementation in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 23–33CrossRefGoogle Scholar
  43. 43.
    Salonen RM, Nyyssonen K, Kaikkonen J, et al. Six year effect of combined vitamin C and E suppliemtation on atherosclerotic progression: ASAP study. Circulation 2003; 107: 947–53PubMedCrossRefGoogle Scholar
  44. 44.
    Meagher EA, Barry OP, Lawson JA, et al. Effects of vitamin E on lipid peroxidation in healthy persons. JAMA 2001; 285: 1178–82PubMedCrossRefGoogle Scholar
  45. 45.
    Carr AC, Zhu BZ, Frei B. Potential antiatherogenic mechanisms of ascorbate (vitamin C) and alpha-tocopherol (vitamin E). Circ Res 2000; 87: 349–54PubMedCrossRefGoogle Scholar
  46. 46.
    Machlin LJ. Vitamin E. In: Machlin LJ, editor. Handbook of vitamins. New York: Marcel Decker, 1991: 99-144Google Scholar
  47. 47.
    Cohn W. Bioavailability of vitamin E. Eur J Clin Nutr 1997; 51: S80–5PubMedGoogle Scholar
  48. 48.
    MacMahon MT, Neale G. The absorption of alpha-tocopherol in control subjects and in patients with intestinal malabsorption. Clin Sci 1970; 38: 197–210PubMedGoogle Scholar
  49. 49.
    Blomstrand R, Forsgren L. Labelled tocopherols in man: intestinal absorption and thoracic-duct lymph transport of dl-alphatocopheryl-3,4-14C2 acetate, dl-alpha-tocopheramine-3,4-14C2 dl-alpha-tocopherol-(5-methyl-3H) and N-(methyl-3H)-dl-gamma-tocopheramine. Int Z Vitaminforsch 1968; 38: 328–44PubMedGoogle Scholar
  50. 50.
    Burton GW, Ingold KU, Foster DO, et al. Comparison of free alpha-tocopherol and alpha-tocopheryl acetate as sources of vitamin E in rats and humans. Lipids 1988; 23: 834–40PubMedCrossRefGoogle Scholar
  51. 51.
    Traber MG, Burton GW, Hughes L, et al. Discrimination between forms of vitamin E by humans with and without genetic abnormalities of lipoprotein metabolism. J Lipid Res 1992; 33: 1171–82PubMedGoogle Scholar
  52. 52.
    Traber MG, Kayden HJ. Preferential incorporation of alphatocopherol vs gamma-tocopherol in human lipoproteins. Am J Clin Nutr 1989; 49: 517–26PubMedGoogle Scholar
  53. 53.
    Hosomi A, Arita M, Sato Y, et al. Affinity for alpha-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Lett 1997; 409: 105–8PubMedCrossRefGoogle Scholar
  54. 54.
    Handelman GJ, Machlin LJ, Fitch K, et al. Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. J Nutr 1985; 115: 807–13PubMedGoogle Scholar
  55. 55.
    Baker H, Handelman GJ, Short S, et al. Comparison of plasma alpha and gamma tocopherol levels following chronic oral administration of either all-rac-alpha-tocopheryl acetate or RRR-alpha-tocopheryl acetate in normal adult male subjects. Am J Clin Nutr 1986; 43: 382–7PubMedGoogle Scholar
  56. 56.
    Ferslew KE, Acuff RV, Daigneault EA, et al. Pharmacokinetics and bioavailability of the RRR and all racemic stereoisomers of alpha-tocopherol in humans after single oral administration. J Clin Pharmacol 1993; 33: 84–8PubMedGoogle Scholar
  57. 57.
    Cheeseman KH, Holley AE, Kelly FJ, et al. Biokinetics in humans of RRR-alpha-tocopherol: the free phenol, acetate ester, and succinate ester forms of vitamin E. Free Radic Biol Med 1995; 19: 591–8PubMedCrossRefGoogle Scholar
  58. 58.
    Yap SP, Yuen KH, Wong JW. Pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under different food status. J Pharm Pharmacol 2001; 53: 67–71PubMedCrossRefGoogle Scholar
  59. 59.
    Bateman NE, Uccellini DA. Kinetics of D-alpha-tocopherol in a water soluble base in man. J Pharm Pharmacol 1985; 37:728–9PubMedCrossRefGoogle Scholar
  60. 60.
    Julianto T, Yuen KH, Noor AM. Improved bioavailability of vitamin E with self emulsifying formulation. Int J Pharm 2000; 200: 53–7PubMedCrossRefGoogle Scholar
  61. 61.
    Traber MG, Ramakrishnan R, Kayden HJ. Human plasma vitamin E kinetics demonstrate rapid recycling of plasma RRR-α-tocopherol. Proc Natl Acad Sci USA 1994; 91: 10005–8PubMedCrossRefGoogle Scholar
  62. 62.
    Zimmer S, Stocker A, Sarbolouki MN, et al. A novel human tocopherol-assocation protein: cloning, in vitro expression and characterisation. J Biol Chem 2000; 275: 25672–80PubMedCrossRefGoogle Scholar
  63. 63.
    Yamauchi J, Iwamoto T, Kida S, et al. Tocopherol-associated protien is a ligand-dependent transcriptional ctivator. Biochen Biophys Res Commun 2001; 285: 295–9CrossRefGoogle Scholar
  64. 64.
    Wechter WJ, Kantoci D, Murray Jr ED, et al. A new endogenous natriuretic factor: LLU-alpha. Proc Natl Acad Sci U S A 1996; 93: 6002–7PubMedCrossRefGoogle Scholar
  65. 65.
    Parker RS, Sontag TJ, Swanson JE. Cytochrome P4503A-de-pendent metabolism of tocopherols and inhibition by sesamin. Biochem Biophys Res Commun 2000; 277: 531–4PubMedCrossRefGoogle Scholar
  66. 66.
    Swanson JE, Ben RN, Burton GW, et al. Urinary excretion of 2,7,8-trimethyl-2-(β-carboxyl)-6-hydroxychroman is a major route of elimination of γ-tocopherol in humans. J Lipid Res 1999; 40: 665–71PubMedGoogle Scholar
  67. 67.
    Schultz M, Leist M, Eisner A, et al. alpha-Carboxyethyl-6-hydroxychroman as urinary metabolite of vitamin E. Methods Enzymol 1997; 282: 297–310PubMedCrossRefGoogle Scholar
  68. 68.
    Schuelke M, Eisner A, Finckh B, et al. Urinary alpha-tocopherol metabolites in alpha-tocopherol transfer protein-deficient patients. J Lipid Res 2000; 41: 1543–51PubMedGoogle Scholar
  69. 69.
    Traber MG, Rader D, Acuff RV, et al. Vitamin E dose-response studies in humans with use of deuterated RRR-alpha-tocopherol. Am J Clin Nutr 1998; 68: 847–53PubMedGoogle Scholar
  70. 70.
    Burton GW, Traber MG, Acuff RV, et al. Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr 1998; 67: 669–84PubMedGoogle Scholar
  71. 71.
    Acuff RV, Thedford SS, Hidiroglou NN, et al. Relative bioavailability of RRR- and all-rac-alpha tocopheryl acetate in humans: studies using deuterated compounds. Am J Clin Nutr 1994; 60: 397–402PubMedGoogle Scholar
  72. 72.
    Machlin JJ, Gabriel E, Brin M. Biopotency of alpha-tocopherols as determined by curative myopathy bioassay in the rat. J Nutr 1982; 112: 1437–40PubMedGoogle Scholar
  73. 73.
    Weiser H, Vecchi M, Schlachter M. Stereoisomers of alphatocopheryl acetate: III. simultaneous determination of resorption-gestation and myopathy in rats as a means of evaluating biopotency ratios of all-rac- and RRR-alpha-tocopheryl acetate. Int J Vitam Nutr Res 1985; 55: 149–58PubMedGoogle Scholar
  74. 74.
    Hoppe PP, Krennrich G. Bioavailability and potency of naturalsource and all-racemic alpha-tocopherol in the human: a dispute. Eur J Nutr 2000; 39: 183–93PubMedCrossRefGoogle Scholar
  75. 75.
    Van Poppel G. Epidemiological evidence for beta-carotene in prevention of cancer and cardiovascular disease. Eur J Clin Nutr 1996; 50 Suppl. 3: S57–61PubMedGoogle Scholar
  76. 76.
    Christen WG, Glynn RJ, Hennekens CH. Antioxidants and agerelated eye disease: current and future perspectives. Ann Epidemiol 1996; 6: 60–6PubMedCrossRefGoogle Scholar
  77. 77.
    Christen WG, Buring JE, Manson JE, et al. Beta-carotene supplementation: a good thing, a bad thing, or nothing? Curr Opin Lipidol 1999; 10: 29–33PubMedCrossRefGoogle Scholar
  78. 78.
    Kritchevsky SB. Beta-carotene, carotenoids and the prevention of coronary heart disease. J Nutr 1999; 129: 5–8PubMedGoogle Scholar
  79. 79.
    Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta-carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996; 334: 1145–9PubMedCrossRefGoogle Scholar
  80. 80.
    Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996; 334: 1150–6PubMedCrossRefGoogle Scholar
  81. 81.
    Stahl W, Sies H. Lycopene: a biologically important carotenoid for humans? Arch Biochem Biophys 1996; 336: 1–9PubMedCrossRefGoogle Scholar
  82. 82.
    Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 1989; 274: 532–8PubMedCrossRefGoogle Scholar
  83. 83.
    Arab L, Steck S. Lycopene and cardiovascular disease. Am J Clin Nutr 2000; 71 (6 Suppl.): 1691S–5SPubMedGoogle Scholar
  84. 84.
    Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst 1999; 91: 317–31PubMedCrossRefGoogle Scholar
  85. 85.
    Kohlmeier L, Kark JD, Gomez-Garcia E, et al. Lycopene and myocardial infarction risk in the EURAMIC study. Am J Epidemiol 1997; 146: 618–26PubMedCrossRefGoogle Scholar
  86. 86.
    Agarwal S, Rao AV. Tomato lycopene and low-density lipoprotein oxidation: a human intervention study. Lipids 1998; 33: 981–4PubMedCrossRefGoogle Scholar
  87. 87.
    Chopra M, O’Neill ME, Keogh N, et al. Influence of increased fruit and vegetable intake on plasma and lipoprotein carotenoids and LDL oxidation in smokers and nonsmokers. Clin Chem 2000; 46: 1818–29PubMedGoogle Scholar
  88. 88.
    Hininger IA, Meyer-Wenger A, Moser U, et al. No significant effects of lutein, lycopene or beta-carotene supplementation on biological markers of oxidative stress and LDL oxidizability in healthy adult subjects. J Am Coll Nutr 2001; 20: 232–8PubMedGoogle Scholar
  89. 89.
    Sutherland WHF, Walker RJ, De Jong SA, et al. Supplementation with tomato juice increases plasma lycopene but does not alter susceptibility to oxidation of low-density lipoproteins from renal transplant recipients. Clin Nephrol 1999; 52: 30–6PubMedGoogle Scholar
  90. 90.
    Riso P, Pinder A, Santangelo A, et al. Does tomato consumption effectively increase the resistance of lymphocyte DNA to oxidative damage? Am J Clin Nutr 1999; 69: 712–8PubMedGoogle Scholar
  91. 91.
    Miller NJ, Sampson J, Candeias LP, et al. Antioxidant activities of carotenes and xanthophylls. FEBS Lett 1996; 384: 240–2PubMedCrossRefGoogle Scholar
  92. 92.
    Moeller SM, Jacques PF, Blumberg JB. The potential role of dietary xanthophylls in cataract and age-related macular degeneration. J Am Coll Nutr 2000; 19 (5 Suppl.): 522S–7SPubMedGoogle Scholar
  93. 93.
    Moore T, editor. Vitamin A. New York: Elsevier Publishing Company, 1957Google Scholar
  94. 94.
    Castenmiller JJM, West CF. Bioavailability and bioconversion of carotenoids. Annu Rev Nutr 1998; 18: 19–38PubMedCrossRefGoogle Scholar
  95. 95.
    Van het Hof KH, Brouver IA, West CE, et al. Bioavailability of lutein from vegetables is 5 times higher than that of betacarotene. Am J Clin Nutr 1999; 70: 261–8Google Scholar
  96. 96.
    Costantino JP, Kuller LH, Begg L, et al. Serum level changes after administration of a pharmacologic dose of beta-carotene. Am J Clin Nutr 1988; 48: 1277–83PubMedGoogle Scholar
  97. 97.
    Johnson EJ, Qin J, Krinsky NI, et al. Beta-carotene isomers in human serum, breast milk and buccal mucosa cells after continuous oral doses of all-trans and 9-cisbeta-carotene. J Nutr 1997; 127: 1993–9PubMedGoogle Scholar
  98. 98.
    Parker RS, Brenna JT, Swanson JE, et al. Assessing metabolism of beta-[13C]carotene using high-precision isotope ratio mass spectrometry. Methods Enzymol 1997; 282: 130–40PubMedCrossRefGoogle Scholar
  99. 99.
    Tang G, Qin J, Dolnikowski GG, et al. Vitamin A equivalence of beta-carotene in a woman as determined by a stable isotope reference method. Eur J Nutr 2000; 39: 7–11PubMedCrossRefGoogle Scholar
  100. 100.
    Huang C, Tang YL, Chen CY, et al. The bioavailability of betacarotene in stir- or deep-fried vegetables in men determined by measuring the serum response to a single ingestion. J Nutr 2000; 130: 534–40PubMedGoogle Scholar
  101. 101.
    Burri BJ, Neidlinger TR, Clifford AJ. Serum carotenoid depletion follows first-order kinetics in healthy adult women fed naturally low carotenoid diets. J Nutr 2001; 131: 2096–100PubMedGoogle Scholar
  102. 102.
    Stahl W, Schwarz W, Sies H. Human serum concentrations of all-trans beta- and alpha-carotene but not 9-cis beta-carotene increase upon ingestion of a natural isomer mixture obtained from Dunaliella salina (betatene). J Nutr 1993; 123: 847–51PubMedGoogle Scholar
  103. 103.
    Kostic D, White WS, Olson JA. Intestinal absorption, serum clearance and interactions between lutein and beta-carotene when administered to human adults in separate or combined oral doses. Am J Clin Nutr 1995; 62: 604–10PubMedGoogle Scholar
  104. 104.
    Novotny JA, Dueker SR, Zech LA, et al. Compartmental analysis of the dynamics of beta-carotene metabolism in an adult volunteer. J Lipid Res 1995; 36: 1825–38PubMedGoogle Scholar
  105. 105.
    van Lieshout M, West CE, et al. Bioefficacy of beta-carotene dissolved in oil studied in children in Indonesia. Am J Clin Nutr 2001; 73: 949–58PubMedGoogle Scholar
  106. 106.
    Handelman GJ, van Kuijk FJGM, Chatterjee A, et al. Characterization of products formed during the autoxidation of betacarotene. Free Radic Biol Med 1991; 10: 427–37PubMedCrossRefGoogle Scholar
  107. 107.
    Kennedy TA, Lieber DC. Peroxyl radical oxidation of betacarotene: formation of beta-carotene epoxides. Chem Res Toxicol 1991; 4: 290–5PubMedCrossRefGoogle Scholar
  108. 108.
    Arab L, Steck S. Lycopene and cardiovascular disease. Am J Clin Nutr 2000; 71 (6 Suppl.): 1691S–5SPubMedGoogle Scholar
  109. 109.
    Sies H, Stahl W. Lycopene: antioxidant and biological effects and its bioavailability in human. Proc Soc Exp Biol Med 1998; 218: 121–4PubMedGoogle Scholar
  110. 110.
    Stahl H, Sies W. Uptake of lycopene and its geometrical isomers is greater from heat-processed than from unprocessed tomato juice in humans. J Nutr 1992; 122: 2161–6PubMedGoogle Scholar
  111. 111.
    Schierle J, Bretzel W, Buhler I, et al. Content and isomeric ratios of lycopene in food and human blood plasma. Food Chem 1997; 59: 459–65CrossRefGoogle Scholar
  112. 112.
    Yeum KJ, Booth SL, Sadowski JA, et al. Human plasma carotenoid response to the ingestion of controlled diets high in fruits and vegetables. Am J Clin Nutr 1996; 64: 594–602PubMedGoogle Scholar
  113. 113.
    Khachik F, Beecher GR, Smith Jr JC. Lutein, lycopene, and their oxidative metabolites in chemoprevention of cancer. J Cell Biochem Suppl 1995; 22: 236–46PubMedCrossRefGoogle Scholar
  114. 114.
    Khachik F, Spangler CJ, Smith Jr JC. Identification, quantification, and relative concentration of carotenoids and their metabolites in human milk and serum. Anal Chem 1997; 69: 1873–81PubMedCrossRefGoogle Scholar
  115. 115.
    De Waart FG, Schouten EG, Stalenhoef AFH, et al. Serum carotenoids, alpha-tocopherol and mortality risk in a prospective study among Dutch elderly. Int J Epidemiol 2001; 30: 136–43PubMedCrossRefGoogle Scholar
  116. 116.
    Dwyer JH, Navab M, Dwyer KM, et al. Oxygenated carotenoid lutein and progression of early atherosclerosis. The Los Angeles Atherosclerosis Study. Circulation 2001; 103: 2922–7PubMedCrossRefGoogle Scholar
  117. 117.
    Landrum JT, Bone RA, Joa H, et al. A one year study of the macular pigment: the effect of 140 days of a lutein supplement. Exp Eye Res 1997; 65: 57–62PubMedCrossRefGoogle Scholar
  118. 118.
    Yao L, Linag Y, Trahanovsky WS, et al. Use of a 13C tracer to quantify the plasma appearance of a physiological dose of lutein in human plasma. Lipids 2000; 35: 339–48PubMedCrossRefGoogle Scholar
  119. 119.
    Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 1998; 56: 317–33PubMedCrossRefGoogle Scholar
  120. 120.
    Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr 2000; 130 (8S Suppl.): 2073S–85SPubMedGoogle Scholar
  121. 121.
    Pietta PG. Flavonoids as antioxidants. J Nat Prod 2000; 63: 1035–42PubMedCrossRefGoogle Scholar
  122. 122.
    Lairon D, Amiot MJ. Flavonoids in food and natural antioxidants in wine. Curr Opin Lipidol 1999; 10: 23–8PubMedCrossRefGoogle Scholar
  123. 123.
    Riemersma RA, Rice-Evans CA, Tyrrell RM, et al. The flavonoids and cardiovascular health. Q J Med 2001; 94: 277–82CrossRefGoogle Scholar
  124. 124.
    Nijveldt RJ, van Nood E, van Hoorn DEC, et al. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 2001; 74: 418–25PubMedGoogle Scholar
  125. 125.
    Skibola CF, Smith MT. Potential health impacts of excessive flavonoid intake. Free Radic Biol Med 2000; 29: 375–83PubMedCrossRefGoogle Scholar
  126. 126.
    Hertog MGL. Epidemiological evidence on potential health properties of flavonoids. Proc Nutr Soc 1996; 55: 385–97PubMedCrossRefGoogle Scholar
  127. 127.
    Hollman PC, Feskens EJ, Katan MB. Tea flavonols in cardiovascular disease and cancer epidemiology. Proc Soc Exp Biol Med 1999; 220: 198–202PubMedCrossRefGoogle Scholar
  128. 128.
    Hertog MGL, Sweetnam PM, Fehily AM, et al. Antioxidant flavonols and ischemic heart disease in a Welsh population of men: the Caerphilly Study. Am J Clin Nutr 1997; 65: 1489–94PubMedGoogle Scholar
  129. 129.
    Hollman PC, Katan MB. Dietary flavonoids: intake, health effects and bioavailability. Food Chem Toxicol 1999; 37: 937–42PubMedCrossRefGoogle Scholar
  130. 130.
    De Vries JHM, Hollman PCH, Meyboom S, et al. Plasma concentrations and urinary excretion of the antioxidant flavonols quercetin and kaempferol as biomarkers of dietary intake. Am J Clin Nutr 1998; 68: 60–5PubMedGoogle Scholar
  131. 131.
    Chopra M, Fitzsimons PEE, Strain JJ, et al. Nonalcoholic red wine extract and quercetin inhibit LDL oxidation without affecting plasma antioxidant vitamin and carotenoid concentrations. Clin Chem 2000; 46: 1162–70PubMedGoogle Scholar
  132. 132.
    Young JF, Nielsen SE, Haraldsdottir J, et al. Effect of fruit juice intake on urinary quercetin excretion and biomarkers of antioxidative status. Am J Clin Nutr 1999; 69: 87–94PubMedGoogle Scholar
  133. 133.
    Thompson HJ, Heimendinger J, Haegele A, et al. Effect of increased vegetable and fruit consumption on markers of oxidative cellular damage. Carcinogenesis 1999; 20: 2261–6PubMedCrossRefGoogle Scholar
  134. 134.
    O’Reilly JD, Mallet AI, McAnlis GT, et al. Consumption of flavonoids in onions and black tea: lack of effect on F2-isoprostanes and autoantibodies to oxidized LDL in healthy humans. Am J Clin Nutr 2001; 73: 1040–4PubMedGoogle Scholar
  135. 135.
    Beatty ER, O’Reilly JD, England TG, et al. Effect of dietary quercetin on oxidative DNA damage in healthy human subjects. Br J Nutr 2000; 84: 919–25PubMedGoogle Scholar
  136. 136.
    Hollman PC, de Vries JH, van Leeuwen SD, et al. Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. Am J Clin Nutr 1995; 62: 1276–82PubMedGoogle Scholar
  137. 137.
    Walle T, Otake Y, Walle UK, et al. Quercetin glucosides are completely hydrolyzed in ileostomy patients before absorption. J Nutr 2000; 130: 2658–61PubMedGoogle Scholar
  138. 138.
    Day AJ, Mellon F, Barron D, et al. Human metabolism of dietary flavonoids: identification of plasma metabolites of quercetin. Free Radic Res 2001; 35: 941–52PubMedCrossRefGoogle Scholar
  139. 139.
    Graefe EU, Wittig J, Mueller S, et al. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol 2001; 41: 492–9PubMedCrossRefGoogle Scholar
  140. 140.
    Olthof MR, Hollman PC, Vree TB, et al. Bioavailabilities of quercetin-3-glucoside and quercetin-4′-glucoside do not differ in humans. J Nutr 2000; 130: 1200–3PubMedGoogle Scholar
  141. 141.
    Ferry DR, Smith A, Malkhandi J, et al. Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 1996; 2: 659–68PubMedGoogle Scholar
  142. 142.
    Boulton DW, Walle K, Walle T. Extensive binding of the bioflavonoid quercetin to human plasma proteins. J Pharm Pharmacol 1998; 50: 243–9PubMedCrossRefGoogle Scholar
  143. 143.
    Hollman PC, van Trijp JM, Buysman MN, et al. Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man. FEBS Lett 1997; 418: 152–6PubMedCrossRefGoogle Scholar
  144. 144.
    Erlund I, Kosonen T, Alfthan G, et al. Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol 2000; 56: 545–53PubMedCrossRefGoogle Scholar
  145. 145.
    Kim DH, Kim SY, Park SY, et al. Metabolism of quercitrin by human intestinal bacteria and its relation to some biological activities. Biol Pharm Bull 1999; 22: 749–51PubMedCrossRefGoogle Scholar
  146. 146.
    Yang CS, Chen L, Lee MJ, et al. Blood and urine levels of tea catechins after ingestion of different amounts of green tea by human volunteers. Cancer Epidemiol Biomarkers Prev 1998; 7: 351–4PubMedGoogle Scholar
  147. 147.
    Sawai Y, Kohsaka K, Nishiyama Y, et al. Serum concentrations of rutenoside metabolites after oral administration of a rutenoside formulation to humans. Drug Res 1987; 37: 729–32Google Scholar
  148. 148.
    Gross M, Pfeiffer M, Martini M, et al. The quantification of metabolites of quercetin flavonols in human urine. Cancer Epidemiol Biomarkers Prev 1996; 5: 711–20PubMedGoogle Scholar
  149. 149.
    Mannach C, Morand C, Crespy V, et al. Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties. FEBS Lett 1998; 426: 331–6CrossRefGoogle Scholar
  150. 150.
    Bolye SP, Dobson VL, Duthie SJ, et al. Bioavailability and efficiency of rutin as an antioxidant: a human supplementation study. Eur J Clin Nutr 2000; 54: 774–82CrossRefGoogle Scholar
  151. 151.
    Yang CS, Chung JY, Yang G, et al. Tea and tea polyphenols in cancer prevention. J Nutr 2000; 130: 472S–8SPubMedGoogle Scholar
  152. 152.
    Bell JR, Donovan JL, Wong R, et al. (+)-Catechin in human plasma after ingestion of a single serving of reconstituted red wine. Am J Clin Nutr 2000; 71: 103–8PubMedGoogle Scholar
  153. 153.
    Lee MJ, Wang ZY, Li H, et al. Analysis of plasma and urinary tea polyphenols in human subjects. Cancer Epidemiol Biomarkers Prev 1995; 4: 393–9PubMedGoogle Scholar
  154. 154.
    Richelle M, Tavazzi I, Enslen M, et al. Plasma kinetics in man of epicatechin from black chocolate. Eur J Clin Nutr 1999; 53: 22–6PubMedCrossRefGoogle Scholar
  155. 155.
    Chow HH, Cai Y, Alberts DS, et al. Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol Biomarkers Prev 2001; 10: 53–8PubMedGoogle Scholar
  156. 156.
    Sazuka M, Itoi T, Suzuki Y, et al. Evidence for the interaction between (−)-epigallocatechin gallate and human plasma proteins fibronectin, fibrinogen, and histidine-rich glycoprotein. Biosci Biotechnol Biochem 1996; 60: 1317–9PubMedCrossRefGoogle Scholar
  157. 157.
    van het Hof KH, Wiseman SA, Yang CS, et al. Plasma and lipoprotein levels of tea catechins following repeated tea consumption. Proc Soc Exp Biol Med 1999; 220: 203–9CrossRefGoogle Scholar
  158. 158.
    Warden BA, Smith LS, Beecher GR, et al. Catechins are bioavailable in men and women drinking black tea throughout the day. J Nutr 2001; 131: 1731–7PubMedGoogle Scholar
  159. 159.
    Das NP. Studies of flavonoid metabolism; absorption and metabolism of (+)-catechin in man. Biochem Pharmacol 1971; 20: 3435–45PubMedCrossRefGoogle Scholar
  160. 160.
    Hacket AM, Griffiths LA, Wermeille M. The quantitative distribution of 3-O-methyl-[U-14C]catechin in man following oral administration. Xenobiotica 1985; 15: 907–14CrossRefGoogle Scholar
  161. 161.
    Baba S, Osakabe N, Yasuda A, et al. Bioavailability of (−)-epicatechin upon intake of chocolate and cocoa in human volunteers. Free Radic Res 2000; 33: 635–41PubMedCrossRefGoogle Scholar
  162. 162.
    Donovan JL, Bell JR, Kasim-Karakas S, et al. Catechin is present as metabolites in human plasma after consumption of red wine. J Nutr 1999; 129: 1662–8PubMedGoogle Scholar
  163. 163.
    Pietta PG, Simonetti P, Gardana C, et al. Catechin metabolites after intake fo green tea infusions. Biofactors 1998; 8: 111–8PubMedCrossRefGoogle Scholar
  164. 164.
    Rein D, Lotito S, Holt RR, et al. Epicatechin in human plasma: in vivo determination and effect of chocolate consumption on plasma oxidation status. J Nutr 2000; 130: 2109S–14SPubMedGoogle Scholar
  165. 165.
    Fremont L. Biological effects of resveratrol. Life Sci 2000; 66: 663–73PubMedCrossRefGoogle Scholar
  166. 166.
    Bertelli AA, Giovannini L, Stradi R, et al. Kinetics of trans-and cis-resveratrol (3,4′,5-trihydroxystilbene) after red wine oral administration in rats. Int J Clin Pharmacol Res 1996; 16: 77–81PubMedGoogle Scholar
  167. 167.
    German JB, Walzern RL. The health benefits of wine. Annu Rev Nutr 2000; 20: 561–93PubMedCrossRefGoogle Scholar
  168. 168.
    Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: a molecule whose time has come? And gone? Clin Biochem 1997; 30: 91–113PubMedCrossRefGoogle Scholar
  169. 169.
    Jang M, Cai L, Udeani GO, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997; 275: 218–20PubMedCrossRefGoogle Scholar
  170. 170.
    Gusman J, Malonne H, Atassi G. A reappraisal of the potential chemopreventive and chemotherapeutic properties of resveratrol. Carcinogenesis 2001; 22: 1111–7PubMedCrossRefGoogle Scholar
  171. 171.
    Wilson T, Knight TJ, Beitz DC, et al. Reveratrol promotes atherosclerosis in hypercholesterolemic rabbits. Life Sci 1996; 59: 15–21CrossRefGoogle Scholar
  172. 172.
    Wu JM, Wang ZR, Hsieh TC, et al. Mechanism of cardioprotection by resveratrol, a phenolic antioxidant present in red wine. Int J Mol Med 2001; 8: 3–17PubMedGoogle Scholar
  173. 173.
    Hung LM, Chen JK, Huang SS, et al. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res 2000; 47: 549–55PubMedCrossRefGoogle Scholar
  174. 174.
    Esti M, Cinquanta L, La Notte E. Phenolic compounds in different olive varieties. J Agric Food Chem 1998; 46: 32–5PubMedCrossRefGoogle Scholar
  175. 175.
    Manna C, Della Ragione F, Cucciolla V, et al. Biological effects of hydroxytyrosol, a polyphenol from olive oil endowed with antioxidant activity. Adv Exp Med Biol 1999; 472: 115–30PubMedGoogle Scholar
  176. 176.
    Visioli F, Galli C, Plasmati E, et al. Olive phenol hydroxytyrosol prevents passive smoking-induced oxidative stress. Circulation 2000; 102: 2169–71PubMedCrossRefGoogle Scholar
  177. 177.
    Coni E, Di Benedetto R, Di Pasquale M, et al. Protective effect of oleuropein, an olive oil biophenol, on low density lipoprotein oxidizability in rabbits. Lipids 2000; 35: 45–54PubMedCrossRefGoogle Scholar
  178. 178.
    Visioli F, Caruso D, Galli C, et al. Olive oils rich in natural catecholic phenols decrease isoprostane excretion in humans. Biochem Biophys Res Commun 2000; 278: 797–9PubMedCrossRefGoogle Scholar
  179. 179.
    Bonanome A, Pagnan A, Caruso D, et al. Evidence of postprandial absorption of olive oil phenols in humans. Nutr Metab Cardiovasc Dis 2000; 10: 111–20PubMedGoogle Scholar
  180. 180.
    Miro-Casas E, Albaladejo MF, Covas MI, et al. Capillary gas chromatography-mass spectrometry quantitative determination of hydroxytyrosol and tyrosol in human urine after olive oil intake. Anal Biochem 2001; 294: 63–72PubMedCrossRefGoogle Scholar
  181. 181.
    Caruso D, Visioli F, Patelli R, et al. Urinary excetion of olive oil phenols and their metabolites in humans. Metabolism 2001; 50: 1426–8PubMedCrossRefGoogle Scholar
  182. 182.
    Visioli F, Galli C, Bornet F, et al. Olive oil phenolics are dosedependently absorbed in humans. FEBS Lett 2000; 468: 159–60PubMedCrossRefGoogle Scholar
  183. 183.
    Pfuetze KD, Dujovne CA. Probucol. Curr Atheroscler Rep 2000; 2: 47–57PubMedCrossRefGoogle Scholar
  184. 184.
    Tardif JC, Cote G, Lesperance J, et al. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty: Multivitamins and Probucol Study Group. N Engl J Med 1997; 337: 365–72PubMedCrossRefGoogle Scholar
  185. 185.
    Azevedo LCP, Pedro MA, Souza LC, et al. Oxidative stress as a signaling mechanism of the vascular response to injury: the redox hypothesis of restenosis. Cardiovasc Res 2000; 47: 436–45PubMedCrossRefGoogle Scholar
  186. 186.
    Walldius G, Regnström J, Nilsson J, et al. The role of lipids and antioxidative factors for the development of atherosclerosis. The Probucol Quantitative Swedish Trial (PQRST). Am J Cardiol 1993; 71: 15B–9BPubMedCrossRefGoogle Scholar
  187. 187.
    McDowell IF, Brennan GM, McEneny J, et al. The effect of probucol and vitamin E treatment on the oxidation of lowdensity lipoprotein and forearm vascular responses in humans. Eur J Clin Invest 1994; 24: 759–65PubMedCrossRefGoogle Scholar
  188. 188.
    Regnström J, Walldius G, Nilsson S, et al. The effect of probucol on low density lipoprotein oxidation and femoral atherosclerosis. Atherosclerosis 1996; 125: 217–29PubMedGoogle Scholar
  189. 189.
    Zimetbaum P, Eder H, Frishman W. Probucol: pharmacology and clinical application. J Clin Pharmacol 1990; 30: 3–9PubMedGoogle Scholar
  190. 190.
    Means ED. 21-Aminosteroids (’lazaroids’). Adv Exp Biol Med 1994; 366: 307–12CrossRefGoogle Scholar
  191. 191.
    Kavanagh RJ, Kam PCA. Lazaroids: efficacy and mechanism of action of the 21-aminosteroids in neuroprotection. Br J Anaesth 2001;86: 110–9PubMedCrossRefGoogle Scholar
  192. 192.
    Tirilazad International Steering Committee. Tirilazad mesylate in acute ischemic stroke: a systematic review. Stroke 2000; 32: 2257–65Google Scholar
  193. 193.
    Marshall LF, Maas AI, Marshall SB, et al. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg 1998; 89: 519–25PubMedCrossRefGoogle Scholar
  194. 194.
    Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. JAMA 1997; 277: 1597–604PubMedCrossRefGoogle Scholar
  195. 195.
    Kassell NF, Haley Jr EC, Apperson-Hansen C, et al. Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg 1996; 84: 221–8PubMedCrossRefGoogle Scholar
  196. 196.
    Haley Jr EC, Kassell NF, Apperson-Hansen C, et al. A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America. J Neurosurg 1997; 86: 467–74PubMedCrossRefGoogle Scholar
  197. 197.
    Lanzino G, Kassell NF. Double-blind, randomized, vehiclecontrolled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage: Part II. a cooperative study in North America. J Neurosurg 1999; 90: 1018–24PubMedCrossRefGoogle Scholar
  198. 198.
    Lanzino G, Kassell NF, Dorsch NW, et al. Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage: Part I. a cooperative study in Europe, Australia, New Zealand, and South Africa. J Neurosurg 1999; 90: 1011–7PubMedCrossRefGoogle Scholar
  199. 199.
    Fleishaker JC, Peters GR. Pharmacokinetics of tirilazad and U-89678 in ischemic stroke patients receiving a loading regimen and maintenance regimen of 10 mg/kg/day of tirilazad. J Clin Pharmacol 1996; 36: 809–13PubMedGoogle Scholar
  200. 200.
    Fleishaker JC, Peters GR, Catcher KS. Evaluation of the pharmacokinetic and tolerability of tirilazad mesylate, a 21-aminosteroid free radical scavenger: I. single-dose administration. J Clin Pharmacol 1993; 33: 175–81PubMedGoogle Scholar
  201. 201.
    Fleishaker JC, Peters GR, Cathcart KS, et al. Evaluation of the pharmacokinetics and tolerability of tirilazad mesylate, a 21-aminosteroid free radical scavenger: II. multiple dose administration. J Clin Pharmacol 1993; 33: 182–90PubMedGoogle Scholar
  202. 202.
    Hulst LK, Fleishaker JC, Peters GR, et al. Effect of age and gender on tirilazad pharmacokinetics in humans. Clin Pharmacol Ther 1994; 55: 378–84PubMedCrossRefGoogle Scholar
  203. 203.
    Bombardt PA, Brewer JF, Johnson MG. Protein binding of tirilazad (U-74006) in human, Sprague-Dawley rat, beagle dog and cynomolgus monkey serum. J Pharmacol Exp Ther 1994; 269: 145–50PubMedGoogle Scholar
  204. 204.
    Cox JW, Larson PG, Wynalda MA, et al. Pharmacokinetics and excretion of the 21-aminosteroid antioxidant U-740006F in rat and perfused rat liver. Drug Metab Dispos 1989; 17: 373–9PubMedGoogle Scholar
  205. 205.
    Lewy AJ. Melatonin as a marker and phase-resetter of circadian rhythms in humans. Adv Exp Med Biol 1999; 460: 425–34PubMedCrossRefGoogle Scholar
  206. 206.
    Reiter RJ, Acuna-Castroviejo D, Tan DX, et al. Free radicalmediated molecular damage: mechanisms for the protective actions of melatonin in the central nervous system. Ann N Y Acad Sci 2001; 939: 200–15PubMedCrossRefGoogle Scholar
  207. 207.
    Cuzzocrea S, Reiter RJ. Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury. Eur J Pharmacol 2001; 426: 1–10PubMedCrossRefGoogle Scholar
  208. 208.
    Maestroni GJ. Therapeutic potential of melatonin in immunodeficiency states, viral disease, and cancer. Adv Exp Med Biol 1999; 467: 217–26PubMedCrossRefGoogle Scholar
  209. 209.
    De Muro RL, Nafziger AN, Blask DE, et al. The absolute bioavailability of oral melatonin. J Clin Pharmacol 2000; 40: 781–4CrossRefGoogle Scholar
  210. 210.
    Di Wl, Kadva A, Atholl J, et al. Variable bioavailability of oral melatonin. N Engl J Med 1997; 336: 1028–9PubMedCrossRefGoogle Scholar
  211. 211.
    Härtter S, Ursing C, Morita S, et al. Orally given melatonin may serve as a probe drug for cytochrome P450 1A2 activity in vivo: a pilot study. Clin Pharmacol Ther 2001; 70: 10–6PubMedCrossRefGoogle Scholar
  212. 212.
    Arteel GE, Sies H. The biochemistry of selenium and the glutathione system. Environ Toxicol Pharmacol 2001; 10: 153–8PubMedCrossRefGoogle Scholar
  213. 213.
    Sies H, Masumoto H. Ebselen as a glutathione peroxidase mimic and as a scavenger of peroxynitrite. Adv Pharmacol 1997, 46Google Scholar
  214. 214.
    Rayman MP. The importance of selenium to human health. Lancet 2000; 356: 233–41PubMedCrossRefGoogle Scholar
  215. 215.
    Kardinaal AFM, Kok FJ, Kohlmeier L, et al. Association between toenail selenium and risk of myocardial infarction in European men. The EURAMIC study. Am J Epidemiol 1997; 145: 373–9PubMedCrossRefGoogle Scholar
  216. 216.
    Neve J. Selenium as a risk factor for cardiovascular disease. J Cardiovasc Risk 1996; 3: 42–7PubMedCrossRefGoogle Scholar
  217. 217.
    Alaejos MS, Diaz Romero FJ, Diaz Romero C. Selenium and cancer: some nutritional aspects. Nutrition 2000; 16: 376–83PubMedCrossRefGoogle Scholar
  218. 218.
    Blot WJ, Li J-Y, Taylor PR, et al. Nutrition intervention trials in Linxian, China. J Natl Cancer Inst 1993; 85: 1483–92PubMedCrossRefGoogle Scholar
  219. 219.
    Clark LC, Combs Jr GF, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. JAMA 1996; 276: 1957–63PubMedCrossRefGoogle Scholar
  220. 220.
    Yu SY, Zhu YJ, Li WG. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res 1997; 56: 117–24PubMedCrossRefGoogle Scholar
  221. 221.
    Delmas-Beauvieux MC, Peuchant E, Couchouron A, et al. The enzymatic antioxidant system in blood and glutathione status in human immunodeficiency virus (HIV)-infected patients: effects of supplementation with selenium or beta-carotene. Am J Clin Nutr 1996; 64: 101–7PubMedGoogle Scholar
  222. 222.
    Yamaguchi T, Sano K, Takakura K, et al. Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Stroke 1998; 29: 12–7PubMedCrossRefGoogle Scholar
  223. 223.
    Saito I, Asano T, Sano K, et al. Neuroprotective effect of an antioxidant, ebselen, in patients with delayed neurological deficits after aneurysmal subarachnoid hemorrhage. Neurosurgery 1998; 42: 269–77PubMedCrossRefGoogle Scholar
  224. 224.
    Finley JW. The retention and distribution by healthy young men of stable isotopes of selenium consumed as selenite, selenate or hydroponically-grown broccoli are dependent on the isotopic form. J Nutr 1999; 129: 865–71PubMedGoogle Scholar
  225. 225.
    Ducros V, Ferry M, Faure P, et al. Distribution of selenium in plasma of French women: relation to age and selenium status. Clin Chem 2000; 46: 731–3PubMedGoogle Scholar
  226. 226.
    Barceloux DG. Selenium. J Toxicol Clin Toxicol 1999; 37: 145–72PubMedCrossRefGoogle Scholar
  227. 227.
    Itoh M, Suzuki KT. Effects of dose on the methylation of selenium to monomethylselenol and trimethylselenonium ion in rats. Arch Toxicol 1997; 71: 461–6PubMedCrossRefGoogle Scholar
  228. 228.
    Janghorbani M, Xia Y, Ha P, et al. Quantitative significance of measuring trimethylselenonium in urine for assessing chronically high intakes of selenium in human subjects. Br J Nutr 1999; 82: 291–7PubMedGoogle Scholar
  229. 229.
    Van Dael P, Davidsson L, Munoz-Box R, et al. Selenium absorption and retention from a selenite- or selenate-fortified milk-based formula in men measured by a stable-isotope technique. Br J Nutr 2001; 85: 157–63PubMedCrossRefGoogle Scholar
  230. 230.
    Moreno-Reyes R, Suetens C, Mathieu F, et al. Osteoarthropathy in rural Tibet in relation to selenium and iodine status. N Engl J Med 1998; 339: 1156–8CrossRefGoogle Scholar
  231. 231.
    Finley JW, Duffield A, Ha P, et al. Selenium supplementation affects the retention of stable isotopes of selenium in human subjects consuming diets low in selenium. Br J Nutr 1999; 82: 357–60PubMedGoogle Scholar
  232. 232.
    Yang GQ, Wang SZ, Zhou RH, et al. Endemic selenium intoxication of humans in China. Am J Clin Nutr 1983; 37: 872–81PubMedGoogle Scholar
  233. 233.
    Janghorbani M, Xia Y, Ha P, et al. Metabolism of selenite in men with widely varying selenium status. J Am Coll Nutr 1999; 18: 462–9PubMedGoogle Scholar
  234. 234.
    Alfthan G, Aro A, Arvilommi H, et al. Selenium metabolism and gluthathione peroxidase activity in healthy Finnish men: effect of selenium yeast, selenite, and selenate. Am J Clin Nutr 1991; 53: 120–5PubMedGoogle Scholar
  235. 235.
    Thomson CD, Robinson MF, Butler JA, et al. Long-term supplementation with selenate and selenomethionine: selenium and glutathione peroxidase (EC1.11.1.9) in blood components of New Zealand women. Br J Nutr 1993; 69: 577–88PubMedCrossRefGoogle Scholar
  236. 236.
    Yang G, Zhou R. Further observations on the human maximum safe dietary selenium intake in a seleniferous area of China. J Trace Elem Electrolytes Health Dis 1994; 8: 159–65PubMedGoogle Scholar
  237. 237.
    Yang G, Yin S, Zhou R, et al. Studies of safe maximal daily dietary Se-intake in a seleniferous area in China: Part II. relation between Se-intake and the manifestation of clinical signs and certain biochemical alterations in blood and urine. J Trace Elem Electrolytes Health Dis 1989; 3: 123–30PubMedGoogle Scholar
  238. 238.
    McCord JM, Fridovich I. Superoxide dismutase: an enzymatic function for erythrocuprein (hemocuprein). J Biol Chem 1969; 244: 6049–55PubMedGoogle Scholar
  239. 239.
    Mates JM, Sanchez-Jimenez F. Antioxidant enzymes and their implications in pathophysiologic processes. Front Biosci 1999; 4: D339–45PubMedCrossRefGoogle Scholar
  240. 240.
    Cudkowicz ME, Warren L, Francis JW, et al. Intrathecal administration of recombinant human Superoxide dismutase 1 in amyotrophic lateral sclerosis: a preliminary safety and pharmacokinetic study. Neurology 1997; 49: 213–22PubMedCrossRefGoogle Scholar
  241. 241.
    Davis JM, Rosenfeld WN, Richter SE, et al. Safety and pharmacokinetics of multiple doses of recombinant human CuZn Superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome. Pediatrics 1997; 100: 24–30PubMedCrossRefGoogle Scholar
  242. 242.
    Flaherty JT, Pitt B, Gruber JW, et al. Recombinant human Superoxide dismutase (h-SOD) fails to improve recovery for ventricular function in patients undergoing coronary angioplasty for acute myocardial infarction. Circulation 1994; 89: 1982–91PubMedCrossRefGoogle Scholar
  243. 243.
    Garcia CE, Kilcoyne CM, Cardillo C, et al. Effect of copperzinc Superoxide dismutase on endothelium-dependent vasodilatation in patients with essential hypertension. Hypertension 1995; 26: 863–8PubMedCrossRefGoogle Scholar
  244. 244.
    Muizelaar JP. Clinical trials with Dismutec™ (pegorgotein, polyethylene glycol-conjugated Superoxide dismutase; PEGSOD) in the treatment of severe closed head injury. Adv Exp Med Biol 1994; 366: 389–400PubMedCrossRefGoogle Scholar
  245. 245.
    Mates JM. Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology. Toxicology 2000; 153: 83–104PubMedCrossRefGoogle Scholar
  246. 246.
    Jadot G, Vaille A, Maldonado J, et al. Clinical pharmacokinetics and delivery of bovine Superoxide dismutase. Clin Pharmacokinet 1995; 28: 17–25PubMedCrossRefGoogle Scholar
  247. 247.
    Marklund S. Distribution of CuZn Superoxide dismutase and Mn Superoxide dismutase in human tissues and extracellular fluids. Acta Physiol Scand Suppl 1980; 492: 19–23PubMedGoogle Scholar
  248. 248.
    Traber MG. The bioavailability bugaboo. Am J Clin Nutr 2000; 71: 1029–30PubMedGoogle Scholar
  249. 249.
    McDermott JH. Antioxidant nutrients: current dietary recommendations and research update. J Am Pharm Assoc (Wash) 2000; 40: 785–99Google Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Edzard Schwedhelm
    • 1
  • Renke Maas
    • 1
  • Raphael Troost
    • 2
  • Rainer H. Böger
    • 1
  1. 1.Institute of Experimental and Clinical Pharmacology, Clinical Pharmacology UnitUniversity Hospital of Hamburg-EppendorfHamburgGermany
  2. 2.Coordination Centre for Clinical TrialsUniversity Hospital MainzMainzGermany
  3. 3.Institute of Experimental and Clinical PharmacologyUniversity Hospital of Hamburg-EppendorfHamburgGermany

Personalised recommendations