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Ideal vitamin C intake

BioFactors 15 (2001) 71–74 71
IOS Press
Ideal vitamin C intake
Mark Levine, Yaohui Wang, Arie Katz, Peter Eck, Oran Kwon, Shenglin Chen,
Je-Hyuk Lee and Sebastian J. Padayatty
Molecular and Clinical Nutrition Section, Digestive Diseases Branch, Building 10 Room 4D52, MSC
1372, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, MD 20892-1372, USA
1. Introduction
To determine ideal vitamin C intake, it is necessary to know the relationship between vitamin C doses
and resulting concentrations in plasma and tissues. Biochemical outcomes can be predicted based on
functions of the vitamin within the concentration ranges measured in subjects at different doses. Clinical
outcomes can be characterized in relation to the measured vitamin concentrations. Recommendations
for ideal vitamin C intake can be guided by these specific criteria [1]:
Biochemical function in relation to concentration
Dietary availability
Dose and steady-state concentrations for plasma
Dose and steady-state concentrations for tissues
Urine excretion: threshold, fractional excretion
Adverse effects and toxicity
Beneficial effects, observations in populations
Prevention of deficiency
Here we summarize dose concentration data for plasma in healthy young male subjects [2].
2. Methods
Study design and details were previously described [2–4]. Briefly, seven healthy male subjects ages
19–26 were hospitalized for 4–6 months on a metabolic ward. Throughout hospitalization they consumed
a diet containing less than 5 mg of vitamin C daily [3]. Deficiencies of other nutrients were prevented
by supplementation. When plasma vitamin C concentrations achieved nadir <10 µM, vitamin C was
administered at 15 mg orally in the fasted state twice daily (30 mg total) until steady state for the dose
Corresponding author: Dr. Mark Levine MD, Building 10 Room 4D52 MSC 1372, National Institutes of Health, Bethesda
MD 20892-1372, USA. Tel.: +1 301 402 5588; Fax: +1 301 402 6436; E-mail:
0951-6433/01/$8.00 2001 IOS Press. All rights reserved
72 M. Levine et al. / Ideal vitamin C intake
was achieved. The following procedures were performed at steady-state: bioavailability sampling; urine
collections for vitamin C, oxalate, urate, creatinine; isolation of circulating neutrophils; apheresis for
isolation of lymphocytes and monocytes; semen collection. When these procedures were complete,
vitamin C dose was increased to 30 mg twice daily (60 mg total) until steady state was achieved, when
the procedures were repeated. In this way subjects received the following doses in mg/day: 30, 60,
100, 200, 400, 1000, and 2500. Vitamin C was measured by HPLC with coulometric electrochemical
3. Results
Plasma data for all 7 subjects at all doses are shown in Fig. 1. These data reveal several aspects of
the relationships between vitamin C doses and resulting concentration. For the depletion phase (0 mg),
the rate of depletion varied several fold. For the first repletion dose (30 mg daily), the mean plasma
concentration at steady state was 8.7+/1.7µM [2]. At 60 mg daily, the plasma concentration for 6
subjects at steady state was approximately 19.2+/3.2µM. One subject had a much higher steady
state concentration, 58.8+/3.1µM. By steady state at 200 mg daily, there was approximately 80%
saturation of plasma for vitamin C. The data show that there was a sigmoidal relationship between dose
and concentration for doses 30–100 mg daily [2]. Data for neutrophils, monocytes, and lymphocytes
indicate that these cell types are saturated at 100–200 mg daily [2]. At doses above 200 mg daily, the
absorbed dose is nearly completely excreted in urine [2].
4. Discussion
Dose concentration data for healthy men reveal that vitamin C concentrations are tightly controlled in
plasma and tissues [2]. At oral doses less than 100 mg daily, small changes in dose produce large changes
in plasma concentrations. Once plasma concentrations of approximately 60–70 µM are achieved, at oral
doses of approximately 200 mg daily, plasma concentrations are kept within a narrow range. Further
dose increases produce little change in resulting steady state concentrations. Vitamin C plasma and
tissue concentrations are tightly controlled as a consequence of absorption, tissue accumulation and
distribution, and renal excretion [2,4]. Why tight control of vitamin C occurs in humans is not currently
known and is worthy of investigation.
Variations between subjects in two aspects were noteworthy: differences in depletion rates, and
difference in repletion at 60 mg daily. Although the reasons for these findings are uncertain, possible
explanations include variations in vitamin C transport, recycling, distribution, utilization, or degradation.
Possible enzymatic explanations include differences in the following: vitamin C sodium dependent
transport by the transporters SVCT1 or SVCT2; dehydroascorbic acid transport by GLUT transporters
GLUT1, GLUT3, or GLUT4; dehydroascorbic acid reduction by glutaredoxin, thioredoxin reductase, or
dehydroascorbic acid reductase; or reduction of glutathione and/or NADPH via glutathione reductase,
6-phosphogluconate dehydrogenase, or other proteins in the pentose shunt.
It was proposed 15 years ago that ideal vitamin intake is best determined based on biochemical,
functional, and/or clinical outcome in relation to vitamin concentration [5]. The data here and in
related publications [2,4] define the concentration ranges of vitamin C found in healthy young men in
plasma and tissues at a wide range of vitamin C doses. Data describing similar dose-concentration
relationships are needed in women, smokers, elderly subjects, and in patients with chronic diseases.
M. Levine et al. / Ideal vitamin C intake 73
Plasma vitamin C (µM)
AM fasting
30 32 56 35 14 9 10 8
Duration of each phase (Days)
0 mg 30 mg 60 mg 100 mg 200 mg 400
0 5 10 15 20 25 30
Scale: Days
Maximum duration of each phase is indicated
Fig. 1. Seven subjects were hospitalized 4–6 months as described in the text [2]. The duration in days for each subject for the
depletion phase (0 mg) and for receipt of 7 different vitamin C doses is shown on the X axis. The maximum duration of each
phase is indicated numerically on the X axis. Fasting vitamin C concentrations for all phases of the study are shown on the Y
axis. Vitamin C doses for each phase are indicated at the top of the figure. Each subject is indicated by a different symbol.
There was variation between subjects in the time taken to reach nadir and in the number of days required to reach steady state
for each dose.
Such information is essential for characterizing biochemical, functional, and/or clinical outcomes in
relationship to vitamin C concentrations in healthy and ill people. Functional and clinical outcomes are
difficult measures in humans, but perhaps provide the most meaningful justification for ideal vitamin
intake. Sound recommendations for nutrient intake are ideally made on the basis of clinical outcomes
such as improvement in the quality of life, or reduction in morbidity or mortality. In the absence of such
information, surrogate markers and dose concentration relationships can be used to deduce ideal intake.
Every effort should be made to use surrogate markers that are known to influence or determine clinical
To date, the only clear clinical benefit of vitamin C ingestion is to prevent scurvy. Direct beneficial
effects of vitamin C in populations are controversial for many diseases including cancer, cataract, and
heart disease. However, ingestion of five servings of fruits and vegetables daily is strongly associated
with protection against cancers of the GI andrespiratory tracts, with potential benefitin preventing heart
disease. Five servings of fruits and vegetablesprovide 210–280 mg of vitamin C daily. Taken together,
the available data suggest that ideal vitamin C intake is 200 mg daily, from a variety of fresh fruits and
vegetables [1].
[1] M. Levine, S.C. Rumsey, R.C. Daruwala, J.B. Park and Y. Wang, Criteria and recommendations for vitamin C intake,
J.A.M.A. 281 (1999), 1415–1423.
74 M. Levine et al. / Ideal vitamin C intake
[2] M. Levine, C. Conry-Cantilena and Y. Wang et al., Vitamin C pharmacokinetics in healthy volunteers: evidence for a
Recommended Dietary Allowance, Proc. Natl. Acad. Sci. USA 93 (1996), 3704–3709.
[3] J. King, Y. Wang, R.W. Welch, K.R. Dhariwal, C. Conry-Cantilena and M. Levine, Use of a new vitamin C-deficient diet
in a depletion/repletion clinical trial, Am. J. Clin. Nutr. 65 (1997), 1434–1440.
[4] J.F. Graumlich, T.M. Ludden, C. Conry-Cantilena, L.R. Jr. Cantilena LR, Y. Wang and M. Levine, Pharmacokinetic
model of ascorbic acid in healthy male volunteers during depletion and repletion, Pharmaceutical Research 14 (1997),
[5] M. Levine, New concepts in the biology and biochemistry of ascorbic acid, N. Engl. J. Med. 314 (1986), 892–902.
... UDP: Uridina difosfato, NAD: Nicotinamida dinucleótido, NADP: Nicotinamida dinucleótido fosfato. 300 mg/Kg diarios 9,10 . Este valor es 300 veces superior a la IDR en humanos y revela la eficiencia y relevancia de los sistemas de reciclaje de vitamina C en especies incapaces de sintetizarla. ...
... frutas y vegetales que presentan niveles de vitamina C sobre los 40 mg/100 g de alimento, pero son consumidos cocidos, como la papaya, el brócoli, los repollos bruselas y las espinacas, perdiendo hasta un 90% de su contenido de vitamina C, según método de cocción 55 . Si bien resulta fácil cumplir con la IDR de vitamina C consumiendo de 3 a 5 porciones de frutas y/o verduras frescas 8,9 , existen varios trabajos en poblaciones estudiantiles de países de Latinoamérica, incluyendo Chile, que demuestran la existencia de una mal nutrición generalizada, asociada a malos hábitos alimentarios y bajo consumo de alimentos saludables 56,57 . Por ejemplo, un estudio que incluyó jóvenes de 54 instituciones de educación superior de 11 regiones de Chile, reveló que sólo el 9,3% tiene una dieta saludable 57 , mientras que nuestros datos preliminares, de un estudio realizado sobre 350 estudiantes universitarios de Concepción, revelan que un 25% tiene una alimentación saludable (datos no publicados). ...
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Vitamin C is a well-known antioxidant. Its intake has been associated with a number of benefits, some of which lack a scientific basis. This review summarizes important biological aspects that determine vitamin C homeostasis, discusses the available information on its possible beneficial effects and its intake in various countries, with special emphasis on some risk groups. The beneficial effects of this vitamin in inflammation, cancer and cardiovascular disease are also summarized, as well as its role as immuno-modulator and epigenetic regulator. Dietary sources of vitamin C and the factors that influence its stability are also presented. Finally, an overview of the research conducted on healthy lifestyles in Latin-American countries are presented. This research summarized provides evidence of poor eating habits, which could account for a vitamin C hypovitaminosis not yet reported that could be associated with unhealthy ageing and the development of non-transmissible chronic diseases.
... About two decades ago, new knowledge of ascorbate pharmacokinetics spawned the discovery of anti-cancer mechanisms of ascorbate action (Table 1). To provide a foundational basis for dietary recommendations for ascorbic acid, healthy subjects underwent intensive clinical pharmacokinetics and physiology studies, the first studies of this kind for any vitamin (Levine et al., 1996(Levine et al., , 2001. Findings were that oral doses of ascorbic acid over an $80-fold dose range produced plasma concentrations that were tightly controlled by limited gastrointestinal absorption, saturated tissue transporters, and renal reabsorption and excretion (Corpe et al., 2010(Corpe et al., , 2013Levine et al., 1996Levine et al., , 2001Padayatty et al., 2004;Sotiriou et al., 2002). ...
... To provide a foundational basis for dietary recommendations for ascorbic acid, healthy subjects underwent intensive clinical pharmacokinetics and physiology studies, the first studies of this kind for any vitamin (Levine et al., 1996(Levine et al., , 2001. Findings were that oral doses of ascorbic acid over an $80-fold dose range produced plasma concentrations that were tightly controlled by limited gastrointestinal absorption, saturated tissue transporters, and renal reabsorption and excretion (Corpe et al., 2010(Corpe et al., , 2013Levine et al., 1996Levine et al., , 2001Padayatty et al., 2004;Sotiriou et al., 2002). Intravenous (i.v.) administration bypassed tight control until the kidney restored homeostasis. ...
Vitamin C (ascorbic acid, ascorbate), despite controversy, has re-emerged as a promising anti-cancer agent. Recent knowledge of intravenous ascorbate pharmacokinetics and discovery of unexpected mechanisms of ascorbate action have spawned many investigations. Two mechanisms of anti-cancer activity with ascorbate have gained prominence: hydrogen peroxide-induced oxidative stress and DNA demethylation mediated by ten-eleven translocation enzyme activation. Here, we highlight salient aspects of the evolution of ascorbate in cancer treatment, provide insights into the pharmacokinetics of ascorbate, describe mechanisms of its anti-cancer activity in relation to the pharmacokinetics, outline promising preclinical and clinical evidence, and recommend future directions.
... Thus, Vitamin C is considered an antioxidant with enormous potential to prevent the development of oxidative reactions of lipids and macromolecules (Macan, Kraljević, & Raić-Malić, 2019). The RDA of Vitamin C has been defined between 65 and 90 mg/day, with 2000 mg being the upper limit that should not be exceeded to avoid side effects (Levine et al., 2001). Similar to Vitamin A, Vitamin E entails several related compounds known as tocopherols and tocotrienols, vitamins categorized as fatsoluble. ...
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... Under physiological conditions, the amount of DHA in plasma is estimated as <1-2% relative to plasma ascorbate levels (32). The recommended daily dose of vitamin C varies between 75 and 100 mg resulting in physiological plasma levels of 50-100 µmol/l (33,34). However, there are major discrepancies regarding recommendations for dietary vitamin C intake depending on individual physiological and pathophysiological conditions (35). ...
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For glioblastoma, the treatment with standard of care therapy comprising resection, radiation, and temozolomide results in overall survival of approximately 14-18 months after initial diagnosis. Even though several new therapy approaches are under investigation, it is difficult to achieve life prolongation and/or improvement of patient's quality of life. The aggressiveness and progression of glioblastoma is initially orchestrated by the biological complexity of its genetic phenotype and ability to respond to cancer therapy via changing its molecular patterns, thereby developing resistance. Recent clinical studies of pharmacological ascorbate have demonstrated its safety and potential efficacy in different cancer entities regarding patient's quality of life and prolongation of survival. In this review article, the actual glioblastoma treatment possibilities are summarized, the evidence for pharmacological ascorbate in glioblastoma treatment is examined and questions are posed to identify current gaps of knowledge regarding accessibility of ascorbate to the tumor area. Experiments with glioblastoma cell lines and tumor xenografts have demonstrated that high‑dose ascorbate induces cytotoxicity and oxidative stress largely selectively in malignant cells compared to normal cells suggesting ascorbate as a potential therapeutic agent. Further investigations in larger cohorts and randomized placebo‑controlled trials should be performed to confirm these findings as well as to improve delivery strategies to the brain, through the inherent barriers and ultimately to the malignant cells.
... Scorbutic gingivitis (Fig. 2) is reported at levels <10 mg/day [19]. Nevertheless, data on which these recommendations were made is limited and therefore on the basis of more recent evidence, some authorities have recommended that the ideal daily intake of vitamin C should be up to 200 mg from a variety of fresh fruit and vegetables [20][21][22]. ...
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Diet has powerful effects upon inflammatory status, arguably as strong or stronger than microbial plaque. Despite a relationship between diet and periodontal inflammatory markers being established over 30 years ago, it is only recently that the mechanisms underpinning these effects have begun to be examined in detail. Following an analysis of the evidence base in 2011, this review focuses upon the most contemporaneous evidence relating specifically to the micronutrient vitamins C and D and their potential impact upon periodontal disease pathogenesis and/or therapeutic outcomes. The authors bring together both epidemiological and laboratory data and aim to outline avenues for potential studies given the limited number of larger well-conducted clinical interventional trials completed to date.
... Bununla beraber bazı kaynaklar vit C'nin ideal olarak günlük alım miktarının 200 mg olması gerektiğini savunmaktadır. 46 Vit C için doğal kaynaklardan birisi de kivi meyvesidir. Günde iki tane kivi günlük tavsiye edilen 200 mg'lık vit C alımını karşılamaktadır. ...
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Nutritional factors are implicated in several systemic diseases and conditions, including overweight and obesity, hypertension, dyslipidemia, type 2 diabetes, cardiovascular disease, osteoporosis that are associated with periodontitis. Also, periodontitis is associated with low serum/plasma micronutrient levels. In recent years, strong evidence has emerged that diets rich in refined carbohydrates and saturated fats are pro-inflammatory, whereas those rich in polyunsaturated fats (fish oils), antioxidant micronutrients (fruits, berries and vegetables) are anti-inflammatory. Although numerous studies evaluated the relationship between micronutrients and periodontal disease, intervention studies in humans are scarce. In relation to periodontal disease, number of studies have been conducted and include vitamin C, vitamin E (tocopherol), carotenoids, polyphenols, flavonoids and other pyhtonutrients. There is a body of evidence from crosssectional studies that support the potential to improve periodontal outcomes by using dietary antioxidants. This lecture will discuss the possible role of some micronutrients in the etiology and therapy of periodontal diseases and makes recommendations for daily nutritional intake for vitamins and antioxidants.
... Two subjects were studied at one time and the graphs show data collated at the end of all studies. Modified and reproduced with permission from Biofactors (Levine et al, 2001a) and The Proceedings of the National Academy of Sciences (Levine et al, 2001b) ...
Vitamin C (Ascorbic acid, abbreviated as AA; the terms vitamin C and ascorbic acid are used interchangeably) is synthesized by all plants and most animals (Smirnoff et al., 2001). It is a vitamin for humans because the gene for gulonolactone oxidase, the terminal enzyme in the AA synthesis pathway has undergone mutations that make it non-functional (Linster & Van Schaftingen, 2007). Animals that have lost the ability to synthesize ascorbic acid do not have a phylogenetic relationship with each other. These animals include non-human primates, guinea pigs, capybara and some birds and fish (Chaudhuri & Chatterjee, 1969, Chatterjee, 1973, Cueto et al., 2000). Deficiency of ascorbic acid produces the fatal disease scurvy, which can be cured only by the administration of vitamin C. This article is protected by copyright. All rights reserved.
... The recommended dietary allowance (RDA) for men was increased from 60 mg to 90 mg and for women from 60 mg to 75 mg daily [30]. Levine et al [31] reported that the optimal intake of vitamin C should be 200 mg daily from a range of fresh fruits and vegetables. ...
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Periodontitis is an increasing area of interest due to its global prevalence. This inflammatory condition results due to the loss of the critical balance between the virulence factors produced by microorganisms and the inflammatory host response. A number of efforts have been made in the past to address this condition and regain periodontal health. Targeting the root cause by nonsurgical debridement has been considered the gold standard. However, research has shown the possible effects of nutrient deficiency and an imbalanced diet on the periodontium. Therefore, an effort toward the maintenance of optimal conditions as well as improvement of the oral health necessities the introduction of adjunctive nutritional therapy, which can benefit the patients. Antioxidants in the diet have some remarkable benefits and valuable properties that play an irreplaceable role in the maintenance of periodontal health. These have emerged as excellent adjuncts that can enhance the outcomes of conventional periodontal therapy. The aim of this review article is to highlight some of these dietary antioxidants that can make a notable difference by striking a balance between health and disease.
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Vitamin C is a water-soluble antioxidant associated with the prevention of the common cold and is also a cofactor of hydrolases that participate in the synthesis of collagen and catecholamines, and in the regulation of gene expression. In cancer, vitamin C is associated with prevention, progression, and treatment, due to its general properties or its role as a pro-oxidant at high concentration. This review explores the role of vitamin C in cancer clinical trials and the aspects to consider in future studies, such as plasmatic vitamin C and metabolite excretion recording, and metabolism and transport of vitamin C into cancer cells. The reviewed studies show that vitamin C intake from natural sources can prevent the development of pulmonary and breast cancer, and that vitamin C synergizes with gemcitabine and erlotinib in pancreatic cancer. In vitro assays reveal that vitamin C synergizes with DNA-methyl transferase inhibitors. However, vitamin C was not associated with cancer prevention in a Mendelian randomized study. In conclusion, the role of vitamin C in the prevention and treatment of cancer is still an ongoing area of research. It is necessary that new phase II and III clinical trials be performed to collect stronger evidence of the therapeutic role of vitamin C in cancer.
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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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Recommendations for vitamin C intake are under revision by the Food and Nutrition Board of the National Academy of Sciences. Since 1989 when the last recommended dietary allowance (RDA) of 60 mg was published, extensive biochemical, molecular, epidemiologic, and clinical data have become available. New recommendations can be based on the following 9 criteria: dietary availability, steady-state concentrations in plasma in relationship to dose, steady-state concentrations in tissues in relationship to dose, bioavailability, urine excretion, adverse effects, biochemical and molecular function in relationship to vitamin concentration, direct beneficial effects and epidemiologic observations in relationship to dose, and prevention of deficiency. We applied these criteria to the Food and Nutrition Board's new guidelines, the Dietary Reference Intakes, which include 4 reference values. The estimated average requirement (EAR) is the amount of nutrient estimated to meet the requirement of half the healthy individuals in a life-stage and gender group. Based on an EAR of 100 mg/d of vitamin C, the RDA is proposed to be 120 mg/d. If the EAR cannot be determined, an adequate intake (AI) amount is recommended instead of an RDA. The AI was estimated to be either 200 mg/d from 5 servings of fruits and vegetables or 100 mg/d of vitamin C to prevent deficiency with a margin of safety. The final classification, the tolerable upper intake level, is the highest daily level of nutrient intake that does not pose risk or adverse health effects to almost all individuals in the population. This amount is proposed to be less than 1 g of vitamin C daily. Physicians can tell patients that 5 servings of fruits and vegetables per day may be beneficial in preventing cancer and providing sufficient vitamin C intake for healthy people, and that 1 g or more of vitamin C may have adverse consequences in some people.
This article has no abstract; the first 100 words appear below. ASCORBIC acid, originally called vitamin C, is required for human health.¹ In human beings deprived of ascorbic acid, the deficiency disease scurvy develops and can be life threatening. Although a disease remarkably similar to scurvy was described by the ancient Egyptians,²,³ it was not until 1753 that a Scottish physician, James Lind, systematically described scurvy and its prevention by dietary means.⁴ Even then, the dietary requirements were controversial. For four decades the British navy refused to accept Lind's findings, and countless sailors continued to die unnecessarily from scurvy until lemon juice was finally included in sailors' rations. Research since Lind's . . . I am indebted to David Blank for editorial assistance, to Gordon Cutler for encouragement, and to Shelley Sturman and Harvey Pollard in particular for helpful suggestions and consistent wholehearted support. Source Information From the Laboratory of Cell Biology and Genetics, National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md. Address reprint requests to Dr. Levine at Bldg. 4, Rm. 312, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892.
To conduct an inpatient study on the recommended dietary allowance (RDA) for vitamin C, we developed a unique vitamin C-deficient diet using a nutrient database and selective menus. Fourteen different menus were developed offering > 300 items with 0-2.4 mg vitamin C per serving. During the 4-6 mo volunteers were hospitalized, daily dietary vitamin C was restricted to < or = 5.0 mg. The mean daily dietary vitamin C intake was < 3.9 mg for the seven study subjects. With concurrent supplementation, the diet provided > or = 85% of the RDA for 17 essential nutrients. Within 3 wk of admission the diet induced vitamin C deficiency as indicated by plasma concentrations, which decreased from 23 +/- 6.9 to 6.9 +/- 2.0 mumol/L. Daily intake of vitamin C and five other nutrients was determined by nutrient database analyses. Mean energy, protein, the iron were 105-185% of the RDA and total and saturated fat were 32% and 10% of energy, respectively. Weight and nutritionally relevant indexes remained normal. Dietary adherence, calculated by the number of days with < or = 5.0 mg vitamin C per total study days, was 88-98% per repletion dose. Computer analyses of menu selections permitted individual preferences to be met while restricting vitamin C intake to < or = 5.0 mg/d. There were no complications from the diet during the depletion and repletion phase. With this diet, ascorbic acid pharmacokinetics for escalating doses could be determined in healthy volunteers.
To develop a new pharmacokinetic model for ascorbic acid (vitamin C) since no previously published model describes ascorbic acid absorption and disposition over a broad physiologic range of doses and plasma concentrations. A new model was developed through exploratory simulations. The model was fitted to pharmacokinetic data obtained from seven healthy volunteers who underwent ascorbic acid depletion then gradual repletion. Concentrations of ascorbic acid were measured in plasma and urine. Final pharmacokinetic model parameter estimates were obtained using nonlinear regression analysis. The new model included saturable absorption, distribution and renal tubular reabsorption parameters. The model described ascorbic acid concentrations in plasma, cells, and urine during depletion and gradual repletion phases with a residual error less than 15%. The model was useful for obtaining a new understanding of the likely causes for the complex concentration-time profile observed during gradual repletion. At doses of 200 to 2500 mg per day, the plateau in pre-dose concentrations is largely due to apparent saturation of tissue uptake and less a function of oral bioavailability and renal excretion than previously thought.