Vitamin C metabolites, independent of smoking status, significantly enhance leukocyte, but not plasma ascorbate concentrations
Abstract
Introduction The objective of this study was to test the effects of acute doses of vitamin C alone, calcium ascorbate with vitamin C metabolites, and placebo, on total plasma and leukocyte vitamin C concentrations over 24 hours.Methods A double-blind, placebo-controlled, four-way crossover study was performed consisting of four separate phases lasting 24 hours each and utilizing one of four oral 1000-mg preparations within each phase (one of vitamin C alone, two separate vitamin C formulations of calcium ascorbate with vitamin C metabolites, and placebo). There was a 7-day washout between phases, and blood draws at seven time points within each phase of the study for a total of 28 serologic measurements per subject and 420 total measurements for the entire clinical trial. Vitamin C concentration in plasma and leukocytes were measured by high-performance liquid chromatography at baseline and at six sequential time periods over 24 hours.Results Fifteen healthy males were enrolled, aged 18-39 years; nine were had never smoked and six were chronic smokers. No significant difference in plasma vitamin C levels was observed when comparing the different preparations. However, at 24 hours, calcium ascorbate with metabolites resulted in significantly higher concentrations of vitamin C in leukocytes (P<0.0001) compared with vitamin C alone. These results were similar for both metabolite formulations, and independent of smoking status.Conclusion Regardless of smoking status, vitamin C metabolites may enhance leukocyte utilization of vitamin C itself, despite no consistent difference in plasma levels among the different preparations. A larger clinical investigation is warranted to confirm these preliminary findings, and to determine the clinical relevance of this impact on overall immune function.
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At 24 h, calcium ascorbate with metabolites significantly increased leukocyte vitamin C concentrations compared to ascorbic acid alone (1.3 to 1.7 times higher, p < 0.0001).
“At 24 h, calcium ascorbate with metabolites significantly increased leukocyte vitamin C concentrations compared to ascorbic acid alone (1.3 to 1.7 times higher, p < 0.0001).”
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 [27]
Vitamin C metabolites can enhance leukocyte vitamin C retention without altering plasma levels.
“A significant finding from these studies is that vitamin C metabolites can enhance leukocyte vitamin C retention without altering plasma levels [16,27].”
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 [27]
Vitamin C supplementation enhances ascorbic acid concentration in plasma and leukocytes, with a greater concentration in leukocytes when receiving vitamin C metabolites compared with ascorbic acid alone or placebo.
“Investigation of the effect of acute doses of vitamin C alone, calcium ascorbate with vitamin C metabolites, and placebo on total plasma and leukocyte vitamin C concentrations 24 h post-dosing supports the understanding that vitamin C supplementation enhances ascorbic acid concentration in plasma and leukocytes, with a greater concentration in leukocytes when receiving vitamin C metabolites comp”
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 [27]
Significant differences were found across preparations in leukocyte vitamin C concentrations, favoring Calcium ascorbate EC, but no differences were observed in plasma vitamin C levels.
“Significant differences were found across preparations in leukocyte vitamin C concentrations, favoring Calcium ascorbate EC, but no differences were observed in plasma vitamin C levels [16,27].”
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 [27]
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 [27]
The lower infection risk reported with Calcium ascorbate EC is consistent with reported improvements in immune cell function and in leucocyte vitamin C reported in other studies.
“The lower infection risk reported with Calcium ascorbate EC in [28] is consistent with the reported improvements in immune cell function [30] and in leucocyte vitamin C reported in other studies [16,27].”
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 [27]
Moyad et al. found all vitamin C interventions were significantly different from placebo for vitamin C in both plasma (p < 0.0001) and leukocytes (p < 0.0001).
“All vitamin C interventions were significantly different from placebo for vitamin C in both plasma (p < 0.0001) and leukocytes (p < 0.0001), and there were few significant differences in plasma vitamin C levels across the preparations, regardless of the post-treatment time monitoring period.”
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 [27]
Moyad et al. found few significant differences in plasma vitamin C levels across the preparations, regardless of the post-treatment time monitoring period.
“All vitamin C interventions were significantly different from placebo for vitamin C in both plasma (p < 0.0001) and leukocytes (p < 0.0001), and there were few significant differences in plasma vitamin C levels across the preparations, regardless of the post-treatment time monitoring period.”
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 [27]
Two studies assessed only males.
“Two studies assessed only males [27,31].”
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 [27]
Out of thirteen analyzed studies, eight (62%) did not report any adverse events for the intervention or comparators.
“Out of the thirteen analyzed studies, eight (62%) did not report any adverse events, either for the intervention or the comparators [12,27,30,31,33,35,36,37].”
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 [27]
From the NICE checklist quality assessment of thirteen RCTs, ten (77%) showed low risk of bias, two (15%) high risk, and one (8%) unclear risk.
“From the assessment of the methodological quality of thirteen RCTs, ten (77%) showed a low risk of bias [12,16,27,28,29,30,31,32,35,37,38], two (15%) showed a high risk of bias [33,36] and one (8%) showed an unclear risk of bias [34].”
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 [27]
Only four studies (31%) reported leukocyte vitamin C concentration, three (in four articles) for Calcium ascorbate EC and one for liposomal-encapsulated vitamin C.
“Only four studies (31%) reported leukocyte vitamin C concentration, three (in four articles) for Calcium ascorbate EC [16,27,30,38] and one for liposomal-encapsulated vitamin C [37].”
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 [27]
Calcium ascorbate EC appears to promote better vitamin C retention in leukocytes.
“Calcium ascorbate EC appears to promote better vitamin C retention in leukocytes [16,27].”
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 [27]
Non-linear relations were noted between changes in vitamin C concentration in plasma and leukocytes.
“Non-linear relations were noted between changes in vitamin C concentration in plasma and leukocytes [16,27].”
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 [27]
Studies using Calcium ascorbate EC reported favorable effects on leukocyte vitamin C concentration, showed improved immunity based on cell functions and numbers, and reported fewer colds and a shorter duration of severe cold symptoms compared to placebo.
“Studies using Calcium ascorbate EC reported favorable effects on leukocyte vitamin C concentration [16,27], showed improved immunity (based on cell functions and numbers) [30], and reported fewer colds and a shorter duration of severe cold symptoms compared to placebo [28].”
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 [27]
At the 1000 mg dose, the tested vitamin C interventions were significantly different from placebo regarding both plasma and leukocyte vitamin C concentrations.
“At the 1000 mg dose, the tested vitamin C interventions were significantly different from placebo regarding both plasma and leukocyte vitamin C concentrations [16,27].”
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 [27]
Vitamin C may enter leukocytes by first converting to dehydroascorbic acid and then back to ascorbic acid upon cell entry, which might explain enhanced absorption and bioavailability over 24 h.
“This might be due to a novel mechanism for an enhanced absorption and bioavailability of vitamin C over 24 h, whereby vitamin C enters leukocytes by first converting to dehydroascorbic acid and then back to ascorbic acid upon cell entry [27].”
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 [27]
Four included studies reported vitamin C concentration in both plasma and leukocytes for different formulations; two examined 1000 mg doses and two examined lower doses (250 and 500 mg).
“Four included studies reported vitamin C concentration in both plasma and leukocytes for different formulations. Two studies examined 1000 mg doses [16,27], and two examined lower doses (250 and 500 mg) [30,37].”
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 [27]
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References 49 · Cited by 15
- Authors
- Moyad, M. A., Combs, M. A., Vrablic, A. S., Velasquez, J., Turner, B., & Bernal, S.
- Affiliations
- University of Michigan (US)
- University of California, Los Angeles (US)
- Corresponding author
- Moyad, Mark A.
- Venue
- Advances in Therapy
- Published
- 2008-10
- Volume
- 25
- Issue
- 10
- Pages
- 995-1009
- ISSN
- 0741-238X (ISSN-L)
- 1865-8652
- OpenAlex
- W2074833322
- Cited by
- 15
- References
- 49
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 3 · 2016: 1 · 2012: 1
- FWCI
- 0.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Advances in Therapy (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 › Biochemistry › Phytochemicals and Antioxidant Activities
- Keywords
- vitamin C, calcium ascorbate, plasma vitamin C, smoking status, immune function
- MeSH terms
- Adolescent, Adult, Ascorbic Acid, Aspartic Acid, Chromatography, High Pressure Liquid, Double-Blind Method, Humans, Leukocytes, Male, Smoking, Vitamins, Cross-Over Studies, Young Adult
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