Determination of plasma and leukocyte vitamin C concentrations in a randomized, double-blind, placebo-controlled trial with Ester-C(®)
Open accessAbstract
BACKGROUND: Rapid uptake of vitamin C into blood and retention in tissues are important indicators of the efficacy of vitamin C supplementation and its immune-supporting role. The objective of this study was to evaluate the bioavailability of vitamin C in plasma (reflective of recent intake) and leukocytes (reflective of tissue stores and influences on immune function) from a novel vitamin C formulation, Ester-C(®). METHODS: The study was a double-blind, placebo-controlled, crossover trial. Thirty-six subjects, 18-60 years of age, were randomized to receive placebo (PL, 0 mg vitamin C), ascorbic acid (AA, 1000 mg vitamin C), and Ester-C(®) (EC, 1000 mg vitamin C). Plasma and leukocyte vitamin C were measured baseline and at 2, 4, 8 and 24 h postdose. RESULTS: The concentration and percent change from baseline in plasma were significantly higher with EC at all time points when compared to PL. No significant differences between EC and AA were observed in plasma concentration. Maximum plasma concentration was higher for EC compared to AA (P = 0.039) and PL (P < 0.001). Plasma area under the curve (AUC0-24h) was higher for EC (P < 0.001) compared to PL. The concentration change from baseline in leukocyte vitamin C was increased with EC at 24 h post-dose (P = 0.036) while no significant within-group changes were observed in AA or PL at any time point. The percent change in leukocyte vitamin C concentration was higher for EC at 8 and 24 h compared to AA (P = 0.028 and P = 0.034, respectively) and PL (P = 0.042 and P = 0.036, respectively). CONCLUSIONS: A single dose of EC resulted in favorable percent change in leukocyte vitamin C concentration compared to AA and PL, indicating EC is retained longer within leukocytes. Trial registration ClinicalTrials.gov Identifier NCT01852903.
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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 [16]
The Results (Leukocyte vitamin C; page not provided) report significantly greater percentage changes with Ester-C than with ascorbic acid and placebo at 8 and 24 hours, but the between-group differences in absolute leukocyte concentration changes were not significant. The Results (Plasma vitamin C; page not provided) report no significant difference between Ester-C and ascorbic acid at individual time points; the paper also reports a higher plasma maximum concentration with Ester-C, so the unqualified claim of no plasma differences overstates the finding. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVitamin 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 [16]
The Results and Discussion (page not specified) report greater leukocyte vitamin C retention after Ester-C than after ascorbic acid. They do not support an unqualified claim that plasma levels were unaltered: plasma vitamin C rose with both treatments, and peak plasma concentration was higher with Ester-C, although the overall plasma change did not differ significantly between them. The trial tested Ester-C, not its metabolites separately. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPlasma/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 [16]
The Discussion states that plasma vitamin C concentrations are tightly regulated. The Background says leukocytes can maintain concentrations several times higher than plasma, but the paper does not establish tight regulation in red blood cells or an up-to-100-fold difference between plasma and tissues (pages unavailable). (LLM, conf=0.88)
Experimental — accuracy not yet measuredAt 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 [16]
The Results sections (page unavailable) report that, at the 1000 mg dose, Ester-C differed significantly from placebo in plasma vitamin C changes and in leukocyte percent changes at 8 and 24 hours. They do not report a significant leukocyte difference between ascorbic acid and placebo; no significant within-group leukocyte change was observed with ascorbic acid. Thus the claim is supported for Ester-C, but not for both tested vitamin C interventions. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNon-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 [16]
The Discussion (page unavailable) reports similar plasma vitamin C changes with Ester-C and ascorbic acid but different leukocyte responses, supporting the idea that changes in the two compartments do not simply track each other. The paper does not explicitly report or test a non-linear relationship between plasma and leukocyte concentration changes. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Calcium ascorbate EC has been shown in clinical studies to have a longer retention (up to 24 h) in immune cells (leukocytes).
“This form of vitamin C has a neutral pH (nonacidic) and has been shown in clinical studies to have a longer retention (up to 24 h) in immune cells (leukocytes) [15,16,17].”
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 [16]
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 [16]
Mitmesser et al. found no significant differences between Calcium ascorbate EC and ascorbic acid in plasma concentration.
“No significant differences were found between Calcium ascorbate EC and ascorbic acid in plasma concentration; however, Calcium ascorbate EC resulted in a higher maximum plasma concentration (Cmax of 7.73 ± 3.12 µg/mL vs. 1.83 ± 2.07 µg/mL for placebo [p < 0.001] and 6.37 ± 2.26 µg/mL for ascorbic acid [p = 0.039]).”
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 [16]
Mitmesser et al. found Calcium ascorbate EC resulted in a higher maximum plasma concentration (Cmax of 7.73 ± 3.12 μg/mL vs. 1.83 ± 2.07 μg/mL for placebo [p < 0.001] and 6.37 ± 2.26 μg/mL for ascorbic acid [p = 0.039]).
“No significant differences were found between Calcium ascorbate EC and ascorbic acid in plasma concentration; however, Calcium ascorbate EC resulted in a higher maximum plasma concentration (Cmax of 7.73 ± 3.12 µg/mL vs. 1.83 ± 2.07 µg/mL for placebo [p < 0.001] and 6.37 ± 2.26 µg/mL for ascorbic acid [p = 0.039]).”
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 [16]
Mitmesser et al. found Calcium ascorbate EC led to a sustained retention of leukocyte vitamin C, with percent changes from baseline significantly higher at 8 and 24 h post-dosing compared to ascorbic acid and placebo.
“During the investigational period, Calcium ascorbate EC led to a sustained retention of leukocyte vitamin C, with percent changes from baseline that were significantly higher at 8 and 24 h post-dosing compared to ascorbic acid and placebo.”
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 [16]
Mitmesser et al. found Calcium ascorbate EC resulted in higher plasma concentrations and a greater percent change from baseline compared to placebo at all time points (p = 0.007 for percent change at 24 h, all others p < 0.001).
“Calcium ascorbate EC resulted in higher plasma concentrations and a greater percent change from baseline compared to the placebo at all time points (p = 0.007 for percent change at 24 h, all others p < 0.001).”
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 [16]
Mitmesser et al. found Calcium ascorbate EC showed a significant increase in leukocyte vitamin C concentration at 24 h post-dosing (p = 0.036), unlike ascorbic acid or placebo.
“Calcium ascorbate EC also showed a significant increase in leukocyte vitamin C concentration at 24 h post-dosing (p = 0.036), unlike ascorbic acid or placebo.”
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 [16]
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 [16]
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 [16]
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 [16]
One study reported seven adverse events among 40 participants (four with ascorbic acid, two with Calcium ascorbate EC, one with placebo), none related to the investigational products.
“One study reported seven adverse events among the 40 studied participants (four with ascorbic acid, two with Calcium ascorbate EC, and one with placebo), but none of the adverse events were related to the investigational products [16].”
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 [16]
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 [16]
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 [16]
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Sulasmi, S., Muchlisyam, M., & Haro, G. (2023) · International Journal Of Science Technology & Management · doi:10.46729/ijstm.v4i2.782 · Cited by 1 · see citing works
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A 12‐year‐old boy with petechiae, arthralgias, and muscle weakness
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The Vitamin C Berpengaruh dalam Memperbaiki Kerusakan Hepar Akibat Pemberian Monosodium Glutamat
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- Authors
- Mitmesser, S. H., Ye, Q., Evans, M., & Combs, M.
- Corresponding author
- Ye, Qian
- Venue
- SpringerPlus
- Published
- 2016-07-25
- Volume
- 5
- Issue
- 1
- Pages
- 1161-1161
- ISSN
- 2193-1801 (ISSN-L)
- PMC
- PMC4960105
- OpenAlex
- W2496202077
- Cited by
- 34
- References
- 41
- Citations by year
- 2025: 5 · 2024: 4 · 2023: 8 · 2022: 6 · 2021: 4 · 2020: 5 · 2019: 1 · 2018: 1
- FWCI
- 0.70
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- SpringerPlus (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- NBTY
- 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, bioavailability, plasma vitamin C, tissue retention, immune function, vitamin C supplementation, ascorbyl palmitate
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