Vitamin C pharmacokinetics: Implications for oral and intravenous use
Abstract
BACKGROUND: Vitamin C at high concentrations is toxic to cancer cells in vitro. Early clinical studies of vitamin C in patients with terminal cancer suggested clinical benefit, but 2 double-blind, placebo-controlled trials showed none. However, these studies used different routes of administration. OBJECTIVE: To determine whether plasma vitamin C concentrations vary substantially with the route of administration. DESIGN: Dose concentration studies and pharmacokinetic modeling. SETTING: Academic medical center. PARTICIPANTS: 17 healthy hospitalized volunteers. MEASUREMENTS: Vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g. RESULTS: Peak plasma vitamin C concentrations were higher after administration of intravenous doses than after administration of oral doses (P < 0.001), and the difference increased according to dose. Vitamin C at a dose of 1.25 g administered orally produced mean (+/-sd) peak plasma concentrations of 134.8 +/- 20.6 micromol/L compared with 885 +/- 201.2 micromol/L for intravenous administration. For the maximum tolerated oral dose of 3 g every 4 hours, pharmacokinetic modeling predicted peak plasma vitamin C concentrations of 220 micromol/L and 13 400 micromol/L for a 50-g intravenous dose. Peak predicted urine concentrations of vitamin C from intravenous administration were 140-fold higher than those from maximum oral doses. LIMITATIONS: Patient data are not available to confirm pharmacokinetic modeling at high doses and in patients with cancer. CONCLUSIONS: Oral vitamin C produces plasma concentrations that are tightly controlled. Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated.
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Plasma/serum and red blood cell levels of vitamin C are tightly controlled, and vitamin C levels can differ up to 100-fold between plasma and various tissues.
“Several authors recommend using other blood and tissue markers of vitamin C to predict clinical outcomes, as plasma/serum and red blood cell levels of vitamin C are tightly controlled, and vitamin C levels can differ up to 100-fold between plasma and various tissues [16,27,42,43].”
From Enhanced Vitamin C Delivery: A Systematic Literature Review Assessing the Efficacy and Safety of Alternative Supplement Forms in Healthy Adults (2025) · cites this paper as [42]
In a recent pharmacokinetic study, participants were administered up to 100 g of vitamin C intravenously within a few hours without any reported adverse effects.
“in a recent pharmacokinetic study participants were administered up to 100 g of vitamin C intravenously within a few hours without any reported adverse effects”
From Vitamin C for preventing and treating the common cold (2013) · cites this paper as Padayatty 2004
Concentrations up to 220 μM can be reached for a short time, but this requires a maximum tolerable dose of 3 g every 4 hours.
“Concentrations up to 220 µM can also be reached for a short time, but this requires a maximum tolerable dose of 3 g every 4 hours [64].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [64]
The maximal steady-state, long-term vitamin C plasma levels achievable by oral administration are 70-85 μM.
“The maximal steady-state, long-term vitamin C plasma levels achievable by oral administration are 70–85 µM [5,64].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [64]
Early trials using both intravenous and oral ascorbate reached a peak plasma level of 6 mM, while later trials giving the same dose orally reached under 200 μM.
“In the initial trials, ascorbate was administered both intravenously and orally and achieved a peak plasma concentration of 6 mM. However, in later trials, where the same dose of ascorbate was administered orally, a peak plasma concentration of less than 200 μM was achieved97.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [97]
The route of ascorbate administration, oral versus intravenous, changes the highest plasma concentration that can be reached.
“the differences between oral and intravenous administration routes can affect the maximum achievable plasma concentration in patients.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [97]
The millimolar ascorbate levels required to kill cancer cells are now generally thought achievable only by intravenous delivery.
“It is now widely accepted that the millimolar concentration of ascorbate needed to induce cytotoxicity in cancer cells can be achieved only when administered intravenously97.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [97]
How vitamin C is administered matters, and this accounts for the disagreement between two early trials of vitamin C as a cancer therapy.
“This paper emphasizes the importance of the route of administration of vitamin C and explains why two early clinical trials of vitamin C as an anticancer therapy had conflicting results.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [97]
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Self-citationThe interplay between vitamin C and thyroid
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- Authors
- Padayatty, S. J., Sun, H., Wang, Y., Riordan, H. D., Hewitt, S. M., Katz, A., Wesley, R. A., & Levine, M.
- Affiliations
- National Institutes of Health (US)
- Venue
- Annals of Internal Medicine
- Publisher
- American College of Physicians
- Published
- 2004-04-06
- Volume
- 140
- Issue
- 7
- Pages
- 533-537
- ISSN
- 0003-4819 (ISSN-L)
- 1539-3704
- OpenAlex
- W2159099334
- Cited by
- 992
- References
- 22
- Citations by year
- 2026: 45 · 2025: 43 · 2024: 40 · 2023: 57 · 2022: 74 · 2021: 88 · 2020: 78 · 2019: 52 · 2018: 57 · 2017: 50 · 2016: 37 · 2015: 45 · 2014: 44 · 2013: 59 · 2012: 38
- FWCI
- 15.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (Z01DK054506)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
- Keywords
- vitamin C, pharmacokinetics, route of administration, intravenous administration, oral administration, plasma vitamin C concentration, high-dose vitamin C, anticancer activity, cancer therapy, pharmacokinetic modeling
- MeSH terms
- Administration, Oral, Adult, Antineoplastic Agents, Ascorbic Acid, Female, Humans, Injections, Intravenous, Male, Reference Values
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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