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. In situ kinetics is dependent on characterizing vitamin function in relation to vitamin concentration in human blood and tissues. For vitamin C, this approach depends on exploring vitamin C biochemistry and molecular biology; vitamin C physiology; and vitamin C clinical pharmacokinetics. Goals of clinical physiology and pharmacokinetics studies for vitamin C are to learn how its 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. Utilization may be a fourth contributor to tight control. 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 expanded basis for an RDA for vitamin C, first in healthy people and eventually in disease states. The approach using clinical physiology and intensive pharmacokinetics studies to determine a vitamin recommendation is the first of its kind for any vitamin. Only with this approach could unanticipated discoveries occur, including those for cancer therapeutics and diabetes, described in separate reports.
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