The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Pharmacokinetic Model of Ascorbic Acid in Healthy Male Volunteers During Depletion and Repletion
Abstract
Purpose 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.Methods 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.Results 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%.Conclusions 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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“In daily doses of 30–60 mg, almost no vitamin C is excreted in urine within 24 h, while a dose of 100 mg results in 25% of the dose of vitamin C excreted and doses equalling or above 500 mg are almost entirely excreted [55,57].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [57]
In the citing paper
“The Michaelis constant Km for renal reabsorption of vitamin C in relation to its plasma levels was suggested to be 33 µM, which is approximately in line with the maximum plasma levels [57].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [57]
Citations
Cites
Clinical pharmacokinetics; concepts and applications
(1989) · General Pharmacology The Vascular System · doi:10.1016/0306-3623(89)90348-0 · Cited by 2,232
Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance
Levine, M., Conry-Cantilena, C., Wang, Y., Welch, R. W., Washko, P. W., Dhariwal, K. R., Park, J. B., Lazarev, A., Graumlich, J. F., King, J., et al. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.8.3704 · Cited by 1,325
Self-citationPresent Knowledge in Nutrition
(2012) · doi:10.1002/9781119946045 · Cited by 907
Distribution of ascorbic acid, metabolites and analogues in man and animals
Hornig, D. (1975) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1975.tb29271.x · Cited by 438
Ascorbic acid recycling in human neutrophils
Washko, P., Wang, Y., & Levine, M. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82289-x · Cited by 289
Self-citationAscorbic acid and dehydroascorbic acid measurements in human plasma and serum
Dhariwal, K., Hartzell, W., & Levine, M. (1991) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/54.4.712 · Cited by 262
Self-citationSteady-state turnover and body pool of ascorbic acid in man.
Kallner, A., Hartmann, D., & Hornig, D. (1979) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/32.3.530 · Cited by 222
Bergsten, P., Amitai, G., Kehrl, J. H., Dhariwal, K. R., Klein, H. G., & Levine, M. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)39841-2 · Cited by 196
Self-citationAscorbic Acid Transport and Accumulation in Human Neutrophils
Washko, P., Rotrosen, D., & Levine, M. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)47256-6 · Cited by 190
Self-citationClinical Pharmacokinetics: Concepts and applications.
Bryson, S. M. (1983) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/j.1365-2710.1983.tb00901.x · Cited by 181
Flagged first, then by citations
Research works printed but not linked: 5
- J. King, R. W. Welch, Y. Wang, K. R. Dhariwal, C. Conry-Cantilena, and M. Levine. Am. J. Clin. Nutr. (1997) in press.
- S. L. Beal, and L. B. Sheiner. NONMEM User's Guide Parts I–VI, NONMEM Project Group, Division of Clinical Pharmacology, University of California, San Francisco, 1992.
- Food and Nutrition Board. Recommended Dietary Allowances, 10th ed., National Academy Press, Washington, DC, 1989.
- Food and Nutrition Board. In Committee of Dietary Allowances (eds) Recommended Dietary Allowances, 9th ed., National Academy of Sciences, Washington, DC, 1980, pp. 72–81.
- Food and Nutrition Board. How should the Recommended Dietary Allowances be Revised, National Academy Press, Washington, DC 1994.
Cited by
Sorted by citations
Items 101–172 of 172
Edward, B. (2010) · Pan African Medical Journal · doi:10.4314/pamj.v5i1.56178 · Cited by 16
Moon, S., Lim, S. H., Yun, J.-W., Lee, W., Kim, M.-H., Cho, K., & Ki, S. (2020) · Anesthesia and Pain Medicine · doi:10.17085/apm.2020.15.1.88 · Cited by 15
Levine, M. N., Ebenuwa, I., & Violet, P.-C. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-805378-2.00018-8 · Cited by 17
Self-citationNath, R. G., Wu, M. Y., Emami, A., & Chung, F. (2010) · Nutrition and Cancer · doi:10.1080/01635580903532424 · Cited by 15
Nutritional Contribution of Some Senegalese Forest Fruits Running across Soudano-Sahelian Zone
Ayessou, N. C., Ndiaye, C., Cissé, M., Guèye, M., & Sakho, M. (2011) · Food and Nutrition Sciences · doi:10.4236/fns.2011.26085 · Cited by 15
Beton-Mysur, K., & Brożek-Płuska, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136928 · Cited by 15
Sanookpan, K., Chantaravisoot, N., Kalpongnukul, N., Chuenjit, C., Wattanathamsan, O., Shoaib, S., Pithi Chanvorachote, B., & Buranasudja, V. (2023) · Antioxidants · doi:10.3390/antiox12091775 · Cited by 16
Trial, T. F., Raimann, J. G., Abbas, S. R., Liu, L., Larive, B., Beck, G. J., Kotanko, P., Levin, N. W., & Handelman, G. J. (2019) · BMC Nephrology · doi:10.1186/s12882-019-1311-4 · Cited by 14
Does Short-Term Vitamin C Reduce Cardiovascular Risk in Type 2 Diabetes?
Gutierrez, A., Duran-Valdez, E., Robinson, I., de Serna, D. G., & Schade, D. S. (2013) · Endocrine Practice · doi:10.4158/ep12431.or · Cited by 14
Velcade and Vitamin C: Too Much of a Good Thing?
Catley, L. P., & Anderson, K. C. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-2272 · Cited by 14
The acute effect of high-dose intravenous vitamin C and other nutrients on blood pressure
Ried, K., Travica, N., & Sali, A. (2016) · Blood Pressure Monitoring · doi:10.1097/mbp.0000000000000178 · Cited by 13
San‐Martín‐Martinez, D., Serrano-Lemus, D., Cornejo, V., Gajardo, A. I. J., & Rodrigo, R. (2022) · Clinical Pharmacokinetics · doi:10.1007/s40262-022-01151-0 · Cited by 12
Hypoxic behavior in cells under controlled microfluidic environment
Morshed, A. Z., & Dutta, P. (2017) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2017.01.017 · Cited by 12
Contribution of Blood Orange-Based Beverages to Bioactive Compounds Intake
Licciardello, F., Arena, E., Rizzo, V., & Fallico, B. (2018) · Frontiers in Chemistry · doi:10.3389/fchem.2018.00374 · Cited by 12
Vitamins as drugs: the importance of pharmacokinetics in oral dosing
Alpers, D. (2010) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e32834172c0 · Cited by 12
Impulsive mathematical modeling of ascorbic acid metabolism in healthy subjects
Bachar, M., Raimann, J. G., & Kotanko, P. (2015) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2015.11.030 · Cited by 13
Karim, M. R., & Kadowaki, M. (2017) · Biochimie · doi:10.1016/j.biochi.2017.08.004 · Cited by 12
Exploring the Ascorbate Requirement of the 2-Oxoglutarate-Dependent Dioxygenases
Smith-Díaz, C. C., Das, A. B., Jurkowski, T. P., Hore, T. A., & Vissers, M. C. M. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02342 · Cited by 11
Mane, S. D., & Kamatham, A. N. (2019) · 3 Biotech · doi:10.1007/s13205-019-1628-5 · Cited by 10
Cullen, J. J., Spitz, D. R., & Buettner, G. R. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.03.030 · Cited by 10
Padayatty, S. J., Levine, M., Eck, P., Wang, Y., Song, J. G., Koh, W. S., & Daruwala, R. (2001) · CRC Press eBooks · doi:10.1201/9780203904046.pt3 · Cited by 9
Self-citationOhkura, N., Yoshiba, K., Yoshiba, N., Edanami, N., Ohshima, H., Takenaka, S., & Noiri, Y. (2023) · Scientific Reports · doi:10.1038/s41598-023-28197-9 · Cited by 9
Vitamin C protective plasma value
Krajcovicová-Kudlácková, M., Babinská, K., Valachovičová, M., Pauková, V., Dušinská, M., & Blažíček, P. (2007) · Bratislavské lekárske listy/Bratislava medical journal · doi:10.1007/bf03656979 · Cited by 9
On monotone contraction mappings in modular function spaces
Alfuraidan, M. R., Bachar, M., & Khamsi, M. A. (2015) · Fixed Point Theory and Applications · doi:10.1186/s13663-015-0274-9 · Cited by 8
Higdon, J. V., Frei, B. B., Packer, L., Traber, M. G., & Kraemer, K. (2002) · Cited by 7
The ‘anomalous’ absorption of labelled and unlabelled vitamin C in man
Bluck, L. J. C., Jones, K. S., Coward, W. A., & Bates, C. J. (2005) · British Journal Of Nutrition · doi:10.1079/bjn20051369 · Cited by 7
Bluck, L. J. C., Jones, K. S., & Bates, C. J. (2002) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.653 · Cited by 7
Jensch, H., Setford, S. J., Thomé, N., Srikanthamoorthy, G., Weingärtner, L., Grady, M., Holt, E., & Pfützner, A. (2025) · Sensors · doi:10.3390/s25071985 · Cited by 6
Cho, J. M. (2024) · Human Nutrition & Metabolism · doi:10.1016/j.hnm.2024.200252 · Cited by 6
Treatment of essential hypertension and non-insulin dependent diabetes mellitus with vitamin C
Nimbkar, N. V., & Lateef, F. (2006) · Medical Hypotheses · doi:10.1016/j.mehy.2006.09.029 · Cited by 6
Brock, G. R., & Chapple, I. (2016) · Current Oral Health Reports · doi:10.1007/s40496-016-0116-9 · Cited by 7
Klener, P., Alexander, M. S., Cullen, J. J., Stejskal, V. D. M., Slíva, J., Kotlářová, L., Kostiuk, P., Procházka, Z., & Kučerová, M. (2020) · Journal of Applied Biomedicine · doi:10.32725/jab.2020.003 · Cited by 5
Mathematical Model for Tissue-Level Hypoxic Response in Microfluidic Environment
Morshed, A. Z., & Dutta, P. (2017) · Journal of Biomechanical Engineering · doi:10.1115/1.4037915 · Cited by 5
Hargrove, J. L., Heinz, G., & Heinz, O. (2008) · Dynamic Medicine · doi:10.1186/1476-5918-7-16 · Cited by 5
Vitamin C in Cancer Treatment: Where Pharmacokinetics Speaks
Chen, Q. (2012) · Journal of Drug Metabolism & Toxicology · doi:10.4172/2157-7609.1000e107 · Cited by 5
Lim, S., Oh, Y. I., Jeong, J., Song, K., Koo, T., & Seo, K. (2019) · Journal of Advanced Veterinary and Animal Research · doi:10.5455/javar.2019.f371 · Cited by 4
Targeting Tumor Metabolism to Overcome Radioresistance
Wahl, D. R., Petronek, M. S., Rashmi, R., Floberg, J. M., Allen, B. G., & Schwarz, J. K. (2020) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-030-49701-9_10 · Cited by 4
Ebenuwa, I., Violet, P.-C., Michel, K., Padayatty, S. J., Wang, Y., Tu, H., Wilkins, K. J., Kassaye, S., & Levine, M. (2023) · Clinical Infectious Diseases · doi:10.1093/cid/ciad333 · Cited by 3
Self-citationParra, P., & Rodrigo, R. (2016) · InTech eBooks · doi:10.5772/63658 · Cited by 3
Vitamin C Pharmacokinetics in Healthy Men and Women
Packer, L. (2003) · AOCS Publishing eBooks · doi:10.4324/9780429270710-2 · Cited by 3
Choi, M., Baek, J., Yun, J., Hong, Y., & Park, E. (2025) · Nutrients · doi:10.3390/nu17213331 · Cited by 2
Manipulating redox active metal metabolism to enhance cancer therapy
Petronek, M. S., & Allen, B. G. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-817868-3.00010-x · Cited by 2
Başeğmez, M., & Eryavuz, A. (2021) · Kocatepe Veterinary Journal · doi:10.30607/kvj.901660 · Cited by 3
Anastassakis, K. (2022) · Springer eBooks · doi:10.1007/978-3-031-08057-9_34 · Cited by 2
Metabolic Production of H2O2 in Carcinogenesis and Cancer Treatment
Allen, B. G., & Spitz, D. R. (2016) · Oxidative stress in applied basic research and clinical practice · doi:10.1007/978-3-319-30705-3_6 · Cited by 3
Benzie, I. F. F., & Strain, J. (2003) · Humana Press eBooks · doi:10.1385/1-59259-070-5:133 · Cited by 2
Goncharova, P. S., Davydova, T. K., & Жукова, Н. Г. (2021) · Personalized Psychiatry and Neurology · doi:10.52667/2712-9179-2021-1-2-63-82 · Cited by 1
Recommended Vitamin C Intake: From Molecular Mechanisms to Clinical Application
Levine, M., Rumsey, S. C., Wang, Y., Park, J., Daruwala, R., & Amano, N. (1998) · Springer eBooks · doi:10.1007/978-88-470-2244-7_10 · Cited by 1
Self-citationEFFECTS OF LIFEPAK ® SUPPLEMENTATION ON ANTIOXIDANT STATUS AND LDL- OXIDATION IN HEALTHY NON-SMOKERS
Smidt, C. R., SEIDEHAMEL, R. J., Devaraj, S., & Jialal, I. (2004) · Cited by 1
Arabadzhiev, I. H., Maurer, P., & Stêväo, É. L. D. L. (2020) · Journal of Oral Medicine and Oral Surgery · doi:10.1051/mbcb/2020018 · Cited by 1
Plant Kingdom as Source of Vitamins
Rivière, C., & Hennebelle, T. (2020) · Springer eBooks · doi:10.1007/978-981-13-1745-3_27-1 · Cited by 1
Vitamin C Pharmacokinetics in Healthy Men and Women
Levine, M., Padayatty, S. J., & Wang, Y. (2003) · AOCS Publishing eBooks · doi:10.1201/9781439822173.ch2 · Cited by 1
Self-citationPellman, J., & Sheikh, F. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.12.005
Cellular Redox Activity and Molecular Functions of Ascorbic Acid
Lodge, J. K. (2005) · Oxidative stress and disease · doi:10.1201/9781420028096.ch12
Polireddy, K. (2015) · KU ScholarWorks (The University of Kansas)
Palmitoyl ascorbate-modified liposomes for the treatment of renal cell carcinoma
Deshpande, M. S. (2014) · Digital Repository Service (Northeastern University) · doi:10.17760/d20196652
Rodrigo, R., González‐Montero, J., Parra, P., & Brito, R. (2017) · Wageningen Academic Publishers eBooks · doi:10.3920/978-90-8686-853-7_1
Examining the markers of vitamin C cytotoxicity in pancreatic ductal adenocarcinoma
Warren, C. (2019) · cIRcle (University of British Columbia) · doi:10.14288/1.0377751
Necşulea, A., Veber, P., Boldanova, T., Ng, C. K. Y., Wieland, S. F., & Heim, M. H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.03.433778
Cushing, C. M., Buettner, G. R., Goel, A., & Schultz, M. K. (2012) · doi:10.17077/etd.810wwaw7
Plant Kingdom as Source of Vitamins
Rivière, C., & Hennebelle, T. (2021) · Springer eBooks · doi:10.1007/978-981-15-4148-3_27
Heller, R. (2012) · Wiley eBooks · doi:10.1002/9783527653058.ch4
Lee, W. J. (2019) · Springer eBooks · doi:10.1007/978-94-024-1713-5_1
Wenzel, U. (2003) · Springer eBooks · doi:10.1007/978-3-642-55896-2_6
Frei, B. B., & Higdon, J. V. (2003) · AOCS Publishing eBooks · doi:10.1201/9781439822173.ch1
Oxidative Stress and Pancreatic Cancer
Cullen, J. J. (2011) · Humana Press eBooks · doi:10.1007/978-1-61779-397-4_13
A Vitamin C Renal Leak in Fabry Disease: The Rare Informs the Common
Monti, D. (2023) · Journal of Nutrition · doi:10.1016/j.tjnut.2023.01.033
Park, S. G., & Kim, H. (2024) · Research Square · doi:10.21203/rs.3.rs-3936042/v1
Balvers, M. G. J., de Smit, T. L., Slotegraaf, A. I., Bemelmans, R. H. H., Kolkert, J. L., Schuijt, T. J., & Witkamp, R. F. (2026) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.70307
Overview of Vitamin C and Cancer
González, M. J., & Miranda-Massari, J. R. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1890-4_1
Faulks (2000) · doi:10.1002/(sici)1097-0010(20000515)80:7
Metadata
- Authors
- Graumlich, J. F., Ludden, T. M., Conry-Cantilena, C., Cantilena, L. R., Wang, Y., & Levine, M.
- Affiliations
- Peoria campus of the University of Illinois System (US)
- University of Nebraska Medical Center (US)
- Uniformed Services University of the Health Sciences (US)
- National Institutes of Health (US)
- Corresponding author
- Graumlich, James F.
- Venue
- Pharmaceutical Research
- Published
- 1997-09
- Volume
- 14
- Issue
- 9
- Pages
- 1133-1139
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- OpenAlex
- W1489783301
- Cited by
- 172
- References
- 25
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 12 · 2020: 11 · 2019: 10 · 2018: 5 · 2017: 8 · 2016: 6 · 2015: 9 · 2014: 9 · 2013: 7 · 2012: 9
- FWCI
- 3.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Pharmaceutical Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (224-88-3002)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-92-0032)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Health Sciences › Medicine › Biochemistry (medical) › Phytochemicals and Antioxidant Activities
- Keywords
- vitamin C, pharmacokinetic modeling, vitamin C depletion, saturable absorption, tubular reabsorption, oral bioavailability, healthy men
- MeSH terms
- Adult, Ascorbic Acid, Biological Availability, Humans, Male, Models, Biological, Prospective Studies
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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
