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The Pharmacokinetics of Vitamin C
Open accessAbstract
The pharmacokinetics of vitamin C (vitC) is indeed complex. Regulated primarily by a family of saturable sodium dependent vitC transporters (SVCTs), the absorption and elimination are highly dose-dependent. Moreover, the tissue specific expression levels and subtypes of these SVCTs result in a compartmentalized distribution pattern with a diverse range of organ concentrations of vitC at homeostasis ranging from about 0.2 mM in the muscle and heart, and up to 10 mM in the brain and adrenal gland. The homeostasis of vitC is influenced by several factors, including genetic polymorphisms and environmental and lifestyle factors such as smoking and diet, as well as diseases. Going from physiological to pharmacological doses, vitC pharmacokinetics change from zero to first order, rendering the precise calculation of dosing regimens in, for example, cancer and sepsis treatment possible. Unfortunately, the complex pharmacokinetics of vitC has often been overlooked in the design of intervention studies, giving rise to misinterpretations and erroneous conclusions. The present review outlines the diverse aspects of vitC pharmacokinetics and examines how they affect vitC homeostasis under a variety of conditions.
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![Figure 1 Ingested vitamin C (vitC) is absorbed across the intestinal epithelium primarily by membrane transporters in the apical brush border membrane, either as ascorbate (ASC) by sodium-coupled active transport via the SVCT1 transporter or as dehydroascorbic acid (DHA) through facilitated diffusion via GLUT1 or GLUT3 transporters. Once inside the cell, DHA is efficiently converted to ASC or transported to the blood stream by GLUT1 and GLUT2 in the basolateral membrane, hereby maintaining a low intracellular concentration and facilitating further DHA uptake. ASC is conveyed to plasma by diffusion, possibly also by facilitated diffusion through volume-sensitive anion channels or by yet unidentified active transporters; the precise efflux mechanisms remain unknown. Modified from [5].](/paper-figures/30b9c406cb6340d587918fc070ca6ee9/the-pharmacokinetics-of-vitamin-c-figure-1.jpg)
![Figure 2 The figure illustrates the highly differential distribution of vitC in the body. Several organs have concentration-dependent mechanisms for the retention of vitC, maintaining high levels during times of inadequate supply at the expense of other organs. Particularly protected is the brain. In addition, the concentration-dependent absorption and re-absorption mechanisms contribute to the homeostatic control of the vitC in the body. Modified from [5].](/paper-figures/d5a78ced5a4447b0ac98fbcf6bbb029a/the-pharmacokinetics-of-vitamin-c-figure-2.jpg)
![Figure 3 Tissue accumulation of vitC depends on both local and systemic conditions. The ratios are based on data obtained from guinea pigs that like human cannot synthesize vitC [7]. (a): During sufficiency, tissues accumulate vitC primarily through the sodium-dependent vitC transporters (SVCTs) perhaps with a small contribution from influx of DHA, which is rapidly converted to ASC. (b): During deficiency, prioritized retainment of vitC occurs in, for example the brain, at the expense of other tissues (c): where increased oxidative stress may result in elevated DHA concentrations, limited recycling capacity and poor tissue accumulation through DHA influx.](/paper-figures/9394dadcf9004ab1a863806aecad5b14/the-pharmacokinetics-of-vitamin-c-figure-3.jpg)
![Figure 4 Schematic outline of vitC metabolism. Modified from [21].](/paper-figures/e27cad48a9184520826de553eeed25f0/the-pharmacokinetics-of-vitamin-c-figure-4.jpg)
![Figure 5 In the kidney, vitC is efficiently filtered by glomerulus to the renal tubule lumen. Reabsorption under vitC deficient conditions is primarily achieved by SVCT1 transporters in the apical membrane although diffusion from the luminal surface may also contribute to the overall uptake. As in the intestinal epithelium, ASC is presumably released to the blood stream through diffusion but the extent and mechanisms of this are not known in detail. GLUT2 transporters are located in the basolateral membrane enabling transport of DHA to plasma. Under saturated conditions, vitC is quantitatively excreted. Modified from [5].](/paper-figures/5c716fc4cf3d40cc895b1c8961630e6b/the-pharmacokinetics-of-vitamin-c-figure-5.jpg)
![Figure 6 Relationship between infusion dose of vitC and plasma Cmax in cancer patients as compiled from [13,75]. The data suggests that a linear relationship between dose and Cmax exists for doses between 1 and 70 g/m2 (p < 0.001, r2 > 0.99), while higher doses results do not translate into higher plasma Cmax.](/paper-figures/2f1f8c10900f465c904d464a1c546bb3/the-pharmacokinetics-of-vitamin-c-figure-6.jpg)
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In the citing paper
“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 [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This can be supported by the fact that its isomer, erythorbic acid, which is a poor substrate of SVCT1, reaches similar plasma concentrations as vitamin C [52].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Dehydroascorbic acid can be again transported through the basolateral membrane of these cells by glucose transporters [52].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Smoking decreases the plasma level of vitamin C on an average by 25–50% [52,61,63].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The Michaelis constant Km, i.e., the concentration of vitamin C transported by half of the maximal transport velocity, was reported to be in a wide range from 10 to 200 µM, suggesting a large capacity to absorb dietary vitamin C.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
Experimental — accuracy not yet measured
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In the citing paper
“The need for vitamin C in smokers is higher, but the available studies suggested different recommendations ranging from 35 to 200 mg of additional vitamin C/day needed for smokers [52].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Ex-smoking seems to slightly decrease the levels as well [52,60].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“There are also reports that vitamin C can pass through the blood-brain barrier in the form of dehydroascorbic acid through the glucose transporter GLUT1 [52,53,73].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The elimination half-life of vitamin C is generally about 2 h [52].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The oxidized form of vitamin C, dehydroascorbic acid, is absorbed likely through glucose transporters, and glucose decreases absorption of dehydroascorbic acid.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
The cited source says what the claim attributes to it.
In the citing paper
“Vitamin C is taken up by the cells via SVCT2 (SLC23A2, Figure 2C), which is a close analogue of SVCT1 with which it shares 65% sequence homology.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
The cited source says what the claim attributes to it.
In the citing paper
“Erythrocytes are very active in mediating this reduction [6,52].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
The cited source says what the claim attributes to it.
In the citing paper
“Since the pH of urine is also lower, passive diffusion was suggested but apparently plays a minor, if any, role at all [52,53].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
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In the citing paper
“Its activity is highest at a neutral pH. It drops markedly with increasing acidity [51,52,53,54].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“In any case, the contribution of dehydroascorbic acid to the total vitamin C absorption is probably low [52].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [52]
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Citations
Cites
The Pecking Order of Free Radicals and Antioxidants: Lipid Peroxidation, α-Tocopherol, and Ascorbate
Buettner, G. R. (1993) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1993.1074 · Cited by 2,417
Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance
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Oxidants in Cigarette Smoke Radicals, Hydrogen Peroxide, Peroxynitrate, and Peroxynitritea
Pryor, W. A., & Stone, K. (1993) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1993.tb39148.x · Cited by 1,179
Ascorbic acid: Chemistry, biology and the treatment of cancer
Du, J., Cullen, J. J., & Buettner, G. R. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.06.003 · Cited by 1,106
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Vitamin C pharmacokinetics: Implications for oral and intravenous use
Padayatty, S. J., Sun, H., Wang, Y., Riordan, H. D., Hewitt, S. M., Katz, A., Wesley, R. A., & Levine, M. (2004) · Annals of Internal Medicine · doi:10.7326/0003-4819-140-7-200404060-00010 · Cited by 992
Does vitamin C act as a pro‐oxidant under physiological conditions?
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Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock
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A family of mammalian Na+-dependent L-ascorbic acid transporters
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Doseděl, M., Jirkovský, E., Macáková, K., Krčmová, L., Javorská, L., Pourová, J., Mercolini, L., Remião, F., Nováková, L., Mladěnka, P., et al. (2021) · Nutrients · doi:10.3390/nu13020615 · Cited by 553
Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease
Chadt, A., & Al-Hasani, H. (2020) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-020-02417-x · Cited by 510
RONS and Oxidative Stress: An Overview of Basic Concepts
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Metadata
- Authors
- Lykkesfeldt, J., & Tveden-Nyborg, P.
- Affiliations
- University of Copenhagen (DK)
- Faculty of Health and Medical Sciences, Department of Veterinary and Animal Sciences, University of Copenhagen, DK-1870 Frederiksberg C, Denmark
- Corresponding author
- Lykkesfeldt, Jens
- ORCID
- Lykkesfeldt, Jens
- Venue
- Nutrients
- Publisher
- MDPI AG
- Published
- 2019-10-09
- Volume
- 11
- Issue
- 10
- Pages
- 2412
- ISSN
- 2072-6643 (ISSN-L)
- PMC
- PMC6835439
- OpenAlex
- W2979508643
- Cited by
- 344
- References
- 123
- Citations by year
- 2026: 43 · 2025: 46 · 2024: 46 · 2023: 63 · 2022: 64 · 2021: 53 · 2020: 29
- FWCI
- 4.97
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Nutrients (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- vitamin C, pharmacokinetics, sodium-dependent vitamin C transporters, dose-dependent absorption, tissue distribution, genetic polymorphism, smoking, diet, cancer therapy, sepsis treatment, dosing regimen
- MeSH terms
- Ascorbic Acid, Ascorbic Acid Deficiency, Diffusion, Female, Homeostasis, Humans, Intestinal Absorption, Nutritional Requirements, Pregnancy, Smoking, Tissue Distribution, Sodium-Coupled Vitamin C Transporters
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