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Cited by 1,325Vitamin C and Antioxidants ResearchAntioxidant Activity and Oxidative StressNutrition and Health Studies

Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance

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Levine, M, Conry-Cantilena, C, Wang, Y, Welch, R W, Washko, P W, Dhariwal, K R, Park, J B, Lazarev, A +3 more·1996·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.93.8.3704PMC PMC39676
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Abstract

Determinants of the recommended dietary allowance (RDA) for vitamin C include the relationship between vitamin C dose and steady-state plasma concentration, bioavailability, urinary excretion, cell concentration, and potential adverse effects. Because current data are inadequate, an in-hospital depletion-repletion study was conducted. Seven healthy volunteers were hospitalized for 4-6 months and consumed a diet containing <5 mg of vitamin C daily. Steady-state plasma and tissue concentrations were determined at seven daily doses of vitamin C from 30 to 2500 mg. Vitamin C steady-state plasma concentrations as a function of dose displayed sigmoid kinetics. The steep portion of the curve occurred between the 30- and 100-mg daily dose, the current RDA of 60 mg daily was on the lower third of the curve, the first dose beyond the sigmoid portion of the curve was 200 mg daily, and complete plasma saturation occurred at 1000 mg daily. Neutrophils, monocytes, and lymphocytes saturated at 100 mg daily and contained concentrations at least 14-fold higher than plasma. Bioavailability was complete for 200 mg of vitamin C as a single dose. No vitamin C was excreted in urine of six of seven volunteers until the 100-mg dose. At single doses of 500 mg and higher, bioavailability declined and the absorbed amount was excreted. Oxalate and urate excretion were elevated at 1000 mg of vitamin C daily compared to lower doses. Based on these data and Institute of Medicine criteria, the current RDA of 60 mg daily should be increased to 200 mg daily, which can be obtained from fruits and vegetables. Safe doses of vitamin C are less than 1000 mg daily, and vitamin C daily doses above 400 mg have no evident value.

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  • Most cells contain vitamin C in millimolar concentrations, which is much higher than its plasma concentrations and compared to other vitamins.

    “Interestingly, most cells contain vitamin C in millimolar concentrations, which is much higher than its plasma concentrations, and compared to other vitamins.”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [55]

    The study summary in our copy (section and page not supplied) reports vitamin C concentrations at least 14-fold higher in neutrophils, monocytes, and lymphocytes than in plasma. A cited reference names millimolar concentrations in mononuclear leukocytes. Our copy does not extend these findings to most cells or compare vitamin C concentrations with those of other vitamins. (LLM, conf=0.86)

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  • Vitamin C absorption is not linear; bioavailability decreases with increasing dose, being 100% at 200 mg, averaging 73% at 500 mg, and approximately 50% at 1.25 g.

    “The bioavailability decreases with an increasing dose being 100% in a low dose of 200 mg and dropping to an average of 73% at a dose of 500 mg and to approximately 50% in the dose of 1.25 g [55].”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [55]

    The study summary (section and page unavailable in our copy) says bioavailability was complete for a single 200 mg dose and declined at single doses of 500 mg and higher. It does not give the claimed 73% at 500 mg or approximately 50% at 1.25 g; searches for those values found no supporting passage. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Plasma vitamin C levels increase to a plateau concentration up to doses of about 200-400 mg daily; higher doses increase plasma levels only minimally.

    “The plasma levels increase to this plateau concentration up to doses of about 200–400 mg daily. Higher doses increase plasma levels only minimally [55,65,66].”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [55]

    The study summary (section and page not supplied) says 200 mg daily was the first dose beyond the steep part of the plasma-concentration curve, supporting diminishing gains at higher doses. But it reports complete plasma saturation at 1000 mg daily, not at 200–400 mg; the claimed plateau at that range overstates the finding. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Vitamin C reaches a concentration between 0.5-5 mM in most cells, except erythrocytes, which do not express SVCT2 and have cytosolic levels reflecting plasma levels of about 50 μM.

    “Vitamin C reaches a concentration between 0.5–5 mM in most cells with the exception of erythrocytes, which do not express SVCT2, and, hence, their cytosolic levels reflect plasma levels and are about 50 µM [52,55,68,71].”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [55]

    The study summary (page not provided) reports that neutrophils, monocytes, and lymphocytes contained vitamin C concentrations at least 14-fold higher than plasma. It does not establish the stated 0.5–5 mM range for most cells or address erythrocyte SVCT2 expression and cytosolic levels of about 50 µM. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • In daily doses of 30-60 mg, almost no vitamin C is excreted in urine within 24 h; a dose of 100 mg results in 25% of the dose excreted; doses equalling or above 500 mg are almost entirely excreted.

    “In daily doses of 30–60 mg, almost no vitamin C is excreted in urine within 24 h, while a dose of 100 mg results in 25% of the dose of vitamin C excreted and doses equalling or above 500 mg are almost entirely excreted [55,57].”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [55]

    The study summary (page not specified in our copy) reports no urinary vitamin C excretion in six of seven volunteers until the 100-mg dose, supporting the low-dose portion. It does not give a 25% excretion figure at 100 mg or specify a 24-hour interval. At single doses of 500 mg or more, it says the absorbed amount was excreted—not that almost the entire administered dose was excreted. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Levine, M., Conry-Cantilena, C., Wang, Y., Welch, R. W., Washko, P. W., Dhariwal, K. R., Park, J. B., Lazarev, A., Graumlich, J. F., King, J., & Cantilena, L. R.
Affiliations
  • National Institutes of Health (US)
  • National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1372, USA.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1996-04-16
Volume
93
Issue
8
Pages
3704-3709
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.93.8.3704
PMC
PMC39676
OpenAlex
W1978407431
Cited by
1,325
References
46
Citations by year
2026: 31 · 2025: 44 · 2024: 42 · 2023: 56 · 2022: 55 · 2021: 61 · 2020: 75 · 2019: 55 · 2018: 50 · 2017: 48 · 2016: 35 · 2015: 45 · 2014: 50 · 2013: 64 · 2012: 55
FWCI
36.39
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutrition and Health Studies
Keywords
vitamin C, pharmacokinetics, RDA, dose-response relationship, steady-state plasma concentration, tissue saturation, neutrophils, monocytes, lymphocytes, bioavailability, urinary excretion, oxalate excretion, uric acid excretion
MeSH terms
Adult, Ascorbic Acid, Biological Availability, Humans, Male, National Institutes of Health (U.S.), Nutritional Requirements, Safety, United States, Nutrition Policy

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