Explanation Prior to 2000, recommended dietary allowances (RDAs) for vitamin C and other vitamins were based on preventing deficiency with a margin of safety. We proposed that new RDAs for vitamins, with vitamin C as a model, should be based on concentration-dependent vitamin functions. We termed this concentration-function approach in situ kinetics, with both molecular and clinical components. Some principles of in situ kinetics were adopted by the National Academy of Sciences as part of revised recommendations for all vitamin intakes. Essential clinical components of in situ kinetics are to learn how vitamin C concentrations are achieved in humans as a function of dose, and to reveal the underlying mechanisms. To characterize these relationships, clinical studies were undertaken at the NIH Clinical Center. Healthy young men and women were hospitalized for 5-7 months, and extensive pharmacokinetics data were collected. Many of these data have been published. Based on portions of these clinical data, RDAs for vitamin C in the United States and Canada were revised upward in 2000 by the National Academy of Sciences, and were also increased in Germany, Austria, Denmark, France, Japan, and China. Continuing analyses of these data are on-going. Based on these pharmacokinetics data, we observed that orally ingested vitamin C a wide dose range resulted in tightly controlled plasma and tissue concentrations. Tight control appeared to be mediated by three coordinated physiologic processes: intestinal absorption;tissue transport/accumulation;and renal filtration/reabsorption. Renal filtration and reabsorption appeared to have a central role in tight control. We have therefore developed new modeling techniques to allow us to accurately determine the renal threshold for vitamin C. Data analyzed include thousands of plasma and urine data points obtained from 36 hour bioavailability experiments conducted at steady state at each of 7 different vitamin C doses in 20 subjects. In addition, we have collected data on 30 subjects with a rare genetic disease that involves renal function, as a model to learn whether the renal threshold for vitamin C can change. Studies are on-going to determine whether the vitamin C renal threshold, calculated after extensive data analyses of intensely studied subjects, can be confirmed in 30 other healthy subjects using simple and rapid sampling techniques. When these analyses are complete, we will be able to determine the vitamin C renal threshold in relation to plasma concentration, and the corresponding vitamin C dose that produces this plasma concentration. Such determination of the renal threshold for vitamin C excretion as a function of dose will provide an entirely new basis for an RDA for vitamin C, first in healthy people and eventually in disease states.

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Eck, Peter K; Corpe, Christopher; Levine, Mark A (2017) Temporo-spacial microanatomical distribution of the murine sodium-dependent ascorbic acid transporters Slc23a1 and Slc23a2 in the kidney throughout development. Biochem Cell Biol 95:421-427
Levine, Mark; Violet, Pierre-Christian (2017) Breaking down, starting up: can a vitamin C-enriched gelatin supplement before exercise increase collagen synthesis? Am J Clin Nutr 105:5-7
Padayatty, S J; Levine, M (2016) Vitamin C: the known and the unknown and Goldilocks. Oral Dis 22:463-93
Shatzer, Amber N; Espey, Michael Graham; Chavez, Mayra et al. (2013) Ascorbic acid kills Epstein-Barr virus positive Burkitt lymphoma cells and Epstein-Barr virus transformed B-cells in vitro, but not in vivo. Leuk Lymphoma 54:1069-78
Corpe, Christopher P; Eck, Peter; Wang, Jin et al. (2013) Intestinal dehydroascorbic acid (DHA) transport mediated by the facilitative sugar transporters, GLUT2 and GLUT8. J Biol Chem 288:9092-101
Parrow, Nermi L; Leshin, Jonathan A; Levine, Mark (2013) Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics. Antioxid Redox Signal :
Eck, Peter; Kwon, Oran; Chen, Shenglin et al. (2013) The human sodium-dependent ascorbic acid transporters SLC23A1 and SLC23A2 do not mediate ascorbic acid release in the proximal renal epithelial cell. Physiol Rep 1:e00136
Padayatty, Sebastian J; Levine, Mark (2013) Standard-dose vs high-dose multivitamin supplements for HIV. JAMA 309:545-6
Li, Hongyan; Tu, Hongbin; Wang, Yaohui et al. (2012) Vitamin C in mouse and human red blood cells: an HPLC assay. Anal Biochem 426:109-17
Eisner, Christoph; Ow, Hooisweng; Yang, Tianxin et al. (2012) Measurement of plasma volume using fluorescent silica-based nanoparticles. J Appl Physiol 112:681-7

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