The Pharmacokinetics of Vitamin C - PubMed (original) (raw)

Review

The Pharmacokinetics of Vitamin C

Jens Lykkesfeldt et al. Nutrients. 2019.

Abstract

The pharmacokinetics of vitamin C (vitC) is indeed complex. Regulated primarily by a family of saturable sodium dependent vitC transporters (SVCTs), the absorption and elimination are highly dose-dependent. Moreover, the tissue specific expression levels and subtypes of these SVCTs result in a compartmentalized distribution pattern with a diverse range of organ concentrations of vitC at homeostasis ranging from about 0.2 mM in the muscle and heart, and up to 10 mM in the brain and adrenal gland. The homeostasis of vitC is influenced by several factors, including genetic polymorphisms and environmental and lifestyle factors such as smoking and diet, as well as diseases. Going from physiological to pharmacological doses, vitC pharmacokinetics change from zero to first order, rendering the precise calculation of dosing regimens in, for example, cancer and sepsis treatment possible. Unfortunately, the complex pharmacokinetics of vitC has often been overlooked in the design of intervention studies, giving rise to misinterpretations and erroneous conclusions. The present review outlines the diverse aspects of vitC pharmacokinetics and examines how they affect vitC homeostasis under a variety of conditions.

Keywords: homeostasis; human disease; pharmacokinetics; vitamin C.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Ingested vitamin C (vitC) is absorbed across the intestinal epithelium primarily by membrane transporters in the apical brush border membrane, either as ascorbate (ASC) by sodium-coupled active transport via the SVCT1 transporter or as dehydroascorbic acid (DHA) through facilitated diffusion via GLUT1 or GLUT3 transporters. Once inside the cell, DHA is efficiently converted to ASC or transported to the blood stream by GLUT1 and GLUT2 in the basolateral membrane, hereby maintaining a low intracellular concentration and facilitating further DHA uptake. ASC is conveyed to plasma by diffusion, possibly also by facilitated diffusion through volume-sensitive anion channels or by yet unidentified active transporters; the precise efflux mechanisms remain unknown. Modified from [5].

Figure 2

Figure 2

The figure illustrates the highly differential distribution of vitC in the body. Several organs have concentration-dependent mechanisms for the retention of vitC, maintaining high levels during times of inadequate supply at the expense of other organs. Particularly protected is the brain. In addition, the concentration-dependent absorption and re-absorption mechanisms contribute to the homeostatic control of the vitC in the body. Modified from [5].

Figure 3

Figure 3

Tissue accumulation of vitC depends on both local and systemic conditions. The ratios are based on data obtained from guinea pigs that like human cannot synthesize vitC [7]. (a): During sufficiency, tissues accumulate vitC primarily through the sodium-dependent vitC transporters (SVCTs) perhaps with a small contribution from influx of DHA, which is rapidly converted to ASC. (b): During deficiency, prioritized retainment of vitC occurs in, for example the brain, at the expense of other tissues (c): where increased oxidative stress may result in elevated DHA concentrations, limited recycling capacity and poor tissue accumulation through DHA influx.

Figure 4

Figure 4

Schematic outline of vitC metabolism. Modified from [21].

Figure 5

Figure 5

In the kidney, vitC is efficiently filtered by glomerulus to the renal tubule lumen. Reabsorption under vitC deficient conditions is primarily achieved by SVCT1 transporters in the apical membrane although diffusion from the luminal surface may also contribute to the overall uptake. As in the intestinal epithelium, ASC is presumably released to the blood stream through diffusion but the extent and mechanisms of this are not known in detail. GLUT2 transporters are located in the basolateral membrane enabling transport of DHA to plasma. Under saturated conditions, vitC is quantitatively excreted. Modified from [5].

Figure 6

Figure 6

Relationship between infusion dose of vitC and plasma Cmax in cancer patients as compiled from [13,75]. The data suggests that a linear relationship between dose and Cmax exists for doses between 1 and 70 g/m2 (p < 0.001, _r_2 > 0.99), while higher doses results do not translate into higher plasma Cmax.

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