Factors Affecting Vitamin C Pharmacokinetics: History
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Subjects: Pharmacology & Pharmacy
Contributor:
Jens Lykkesfeldt
,
Pernille Tveden-Nyborg

The pharmacokinetics of vitamin C (vitC) is highly complex. Regulated primarily by a family of saturable sodium dependent vitC transporters (SVCTs), both the absorption and elimination phases display high dose-dependency. Also, tissue specific expression of SVCT subtypes result in a diverse distribution pattern with organ concentrations of vitC at homeostasis ranging from about 0.2 mM up to 10 mM. Unfortunately, the complex pharmacokinetics of vitC has often been overlooked in the design of human intervention studies, giving rise to misinterpretations and erroneous conclusions.

  • vitamin C
  • pharmacokinetics
  • homeostasis
  • human disease

1. Pharmacokinetics of Vitamin C

Humans rely solely on dietary intake for the maintenance of the body pool of vitamin C (vitC). In contrast to the vast majority of vertebrates, in which l-gulonolactone oxidase catalyzes the final step in the biosynthesis of ascorbic acid, evolutionally conserved deletions have made the corresponding gene inactive in primates, flying mammals, guinea pigs, and some bird and fish species, thereby disabling its formation [1]. This evolutionary event may in fact have resulted in an adaptational process where our ability to prevent vitC deficiency has been improved by various measures changing the pharmacokinetics, including more efficient absorption, recycling, and renal reuptake of vitC compared to vitC synthesizing species [2][3].
Pharmacokinetics constitutes the description of absorption, distribution, metabolism, and excretion of drugs. Pharmacokinetics is based on a number of theoretical models, all of which have a set of assumptions that need to be fulfilled for their validity. Compared to a typical orally administered low molecular weight drug, vitC differs in multiple ways with respect to pharmacokinetic properties [4]. Unfortunately, lack of proper attention to particularly the nonlinearity of vitC pharmacokinetics has led to misinterpretation of a major part of the clinical literature as reviewed elsewhere [4][5][6]. The majority of intestinal uptake, tissue distribution, and renal reuptake is handled by the sodium-dependent vitC transporter (SVCT) family of proteins [7] that cotransports sodium ions and ascorbate (ASC) across membranes with the ability to generate considerable concentration gradients [8][9]. It is the differential expression, substrate affinity, and concentration dependency of the SVCTs between organs that gives rise to the unique compartmentalization and nonlinear pharmacokinetics of vitC at physiological levels [10].
The hydrophilic nature of ASC and the likely resulting absence of passive diffusion across biological membranes has puzzled pharmacologists. However, two decades ago, active transport of vitC was found to be essential for life, when Sotiriou et al. showed that SVCT2 knockout mice die immediately after birth from respiratory failure with severe brain hemorrhage [11]. Acknowledging the role of SVCTs in vitC homeostasis has naturally sparked an interest in possible differences in SVCT activity between individuals and potential impact on vitC status. Thus, a number of polymorphisms have been identified, and these may affect the pharmacokinetics of vitC significantly. Although not investigated in clinical studies yet, pharmacokinetic modelling has suggested that several of the identified SVCT alleles result in a lower plasma steady state level and consequently completely altered homeostasis [12] with the lowest saturation level leading to permanent vitC deficiency, i.e., a plasma concentration < 23 µM [5][13].
In contrast to the physiological concentrations achievable by oral ingestion, pharmacological concentrations, i.e., millimolar plasma concentrations, can be reached by parenteral administration, mostly intravenous infusion [14]. Interestingly, the pharmacokinetics of vitC appears to change from zero to first order following high-dose infusion displaying a constant and dose-independent half-life [15].
A final factor contributing to the complexity of vitC pharmacology is its metabolism. Low molecular weight drugs and xenobiotics are normally metabolized by a combination of phase I and II enzymes leading to oxidized and conjugated metabolites with increased water solubility and enhanced clearance. VitC takes part in numerous physiological reactions as an electron donor [16]. Acting both as a specific cofactor or antioxidant, ASC is oxidized to the ascorbyl radical, which subsequently may undergo dismutation to form ASC and dehydroascorbic acid (DHA) [17]. Although DHA has a half-life of only a few minutes [18], it is normally reduced back to ASC by enzymatic means, an intracellular process that is both efficient and quantitative in healthy individuals. However, it has been shown that the recycling process may be inadequate during disease and among smokers, for example, resulting in an increased turnover of vitC [19][20]. Thus, increased intake of vitC may be necessary to achieve homeostasis in high-risk individuals.

2. Factors Affecting Vitamin C Homeostasis and Requirements

As described in detail in the above, vitC homeostasis is tightly controlled in healthy individuals giving rise to a complex relationship between the steady state levels of the various bodily organs and tissues. This interrelationship depends primarily on the availability of vitC in the diet and the specific “configurations” and expression levels of SVCTs of the tissues. However, a number of other factors may interfere with the body’s attempt control the vitC homeostasis, and some major contributors are discussed below.

2.1. Influence of Polymorphisms

With the acknowledgement of the importance of SVCTs for regulation of vitC homeostasis and the evolution of genomic sequencing techniques, it has become clear that a large number of polymorphisms exist that influence the steady state level of vitC. This has been reviewed in detail elsewhere [3], but little is known about the potential clinical impact of these. A Mendelian randomization study in 83,256 individuals from the Copenhagen General Population Study used a genetic variant rs33972313 in Slc23a1 resulting in higher than average vitC status to test if improved vitC status is associated with low risk of ischemic heart disease and all-cause mortality [21]. The authors found that high intake of fruits and vegetables was associated with low risk of ischemic heart disease and all-cause mortality. Effect sizes were comparable for vitC, albeit not significantly. As mentioned earlier, modelling studies have proposed that the functionally poorest SVCT allele identified so far (A772G, rs35817838) results in a plasma saturation level of only one fourth of that of the background population corresponding to a condition of life-long vitC deficiency [12]. It would indeed be interesting to test how this allele compares for morbidity and mortality.

2.2. Smoking

Smoking is a major source of oxidants and estimates have suggested that every puff of a cigarette equals the inhalation of about 1014 tar phase radicals and 1015 gas phase radicals [22]. Not surprisingly, this draws a major toll on the antioxidant defense of the body as demonstrated by a persistent association between tobacco smoke and poor antioxidant status in general, and poor vitC status in particular [19][23]. Active smoking typically depletes the vitC pool by 25–50% compared to never-smokers [24], while environmental tobacco smoke exposure results in a drop of about half that size [25][26]. The direct cause of the smoking-induced vitC depletion has been investigated, and smoking cessation has been shown to immediately restore about half of the vitC depletion observed as a result of smoking [27]. This immediate albeit partial recovery has pointed towards an oxidative stress mediated depletion of vitC caused by smoking. Moreover, both oxidative stress and ASC recycling are induced by smoking regardless of antioxidant intake [20][28]. However, the lack of full recovery suggests that other factors also contribute to the lower vitC status among smokers. Studies have suggested that the difference in vitC status between smokers and nonsmokers is not related to altered pharmacokinetics of vitC [29][30]. However, as smokers in general have a lower intake of fruits and vegetables and a larger intake of fat compared to nonsmokers [31], this may account for the difference in vitC levels observed between ex-smokers and never-smokers [4]. Indeed, an analysis of the Second National Health and Nutrition Examination Survey (NHANES II) confirmed that the vitC intake of smokers is significantly lower than that of nonsmokers, but also that the increased risk of poor vitC status was independent of this lower intake [32].
Various attempts have been made to estimate the amount of vitC needed to compensate for tobacco smoking. Schectman et al. analyzed the NHANES II data, comparing daily intake vs. serum concentrations of vitC among 4182 smokers and 7020 non-smokers. They estimated by regression analysis that smokers would need an additional 130 mg/day to overcome the adverse effect of smoking on vitC status [33]. In a separate analysis, it was concluded that smokers need an intake > 200 mg/day to lower the risk of vitC deficiency to that of nonsmokers [34]. These results were later indirectly supported by Lykkesfeldt et al. using a different approach. Measuring the steady state oxidation ratio of vitC in smokers and nonsmokers, it was shown that in particular smokers with poor vitC status had an increased steady state oxidation of their vitC pool compared to nonsmokers [19]. The authors concluded that smokers need at least 200 mg vitC per day to compensate for the effect of smoking on the oxidation of vitC [19]. These data stand in contrast to previous data by Kallner et al., who used 14C-labelled ASC to estimate the turnover of vitC in smokers [35]. Seventeen male smoking volunteers between 21 and 69 years of age and weighing between 55 and 110 kg received doses from 30 to 180 mg/day and were instructed to ingest a diet completely devoid of vitC. Urinary excretion of radioactivity was used to estimate the vitC pharmacokinetics using a three-compartment model. Based on these data, Kallner et al. concluded that smokers needed only about 35 mg more than nonsmokers per day to compensate for their habit [35]. This recommendation was later adopted by the Institute of Medicine in their dietary reference intakes [36]. However, several problems are associated with the latter study. Namely, radioactivity rather than ASC per se was quantified as a surrogate for vitC excretion. Moreover, only 17 individuals with considerable variation in age and body composition were included in the study. Finally, these studies were carried out prior to the identification of the SVCTs and their importance for the nonlinear pharmacokinetics of vitC at physiological levels. In fact, such a dose-concentration relationship formally rules out the use of compartment as well as noncompartment kinetic modelling, as the fundamental assumption of a terminal first order elimination phase is not fulfilled. Thus, it appears likely that the turnover in smokers may be underestimated by Kallner et al.

2.3. Pregnancy

Several preclinical studies have illustrated the importance of vitC in early development, in particular that of the brain and cognition [37][38][39][40][41]. In humans, studies have shown that poor maternal vitC status results in increased fetal oxidative stress, impaired implantation and increased risk of complications including preeclampsia [42][43]. It is not clear to what extent vitC supplementation may ameliorate this risk. The few controlled studies that have been carried out have produced mixed results [44][45][46][47], but unfortunately, none of them have considered vitC status in the recruitment or group allocation process and they are therefore of limited value.
During pregnancy, the human fetus relies completely on an adequate maternal vitC intake and transplacental transport of vitC. Experimental evidence suggests that this transport is primarily governed by SVCT2 and thus constitutes the primary means of fetal vitC supply [37]. Expectedly, maternal vitC status has been shown to gradually decline from the 1st to 3rd trimester, a change not only explainable by the increased volume of distribution but rather by the selective accumulation across the placenta [48]. Fetal and postnatal steady state concentrations exceed those of the mother, and both during pregnancy and lactation, most authorities recommend an increased intake ranging from 10 to 35 additional mg vitC/day to compensate for this increased draw on maternal resources [36].

2.4. Disease

A plethora of disease conditions, including infectious diseases, cancer, cardiovascular disease, stroke, diabetes, and sepsis, have been associated with poor vitC status (reviewed in [4][6]). Considerable epidemiological evidence has shown vitC deficiency to negatively affect independent risk factors of, for example, cardiovascular disease development [16]. However, causal linkage between disease etiology and vitC status remains scarce, except for that of scurvy [49]. The decreased vitC status in disease is often explained by a combination of a sometimes massively increased turnover due to oxidative stress and inflammation and a decreased dietary intake of vitC associated with the disease [50][51].
An obvious display of increased vitC turnover in critical illness is that large doses are often needed to replete the individual to the level of a healthy control. These doses exceed those necessary to saturate a healthy individual by many-fold [52]. One current example is sepsis patients where systemic inflammation and oxidative stress presumably increases the expenditure of vitC [53][54]. Recently published data on critically ill patients (n = 44, both septic and nonseptic patients) show that actual plasma vitC concentrations are on average 60% lower than the values predicted from patient vitC intake during hospitalization (either enteral or parenterally administered nutrition) [52]. Although several causes of the apparent vitC depletion are likely, e.g., interactions with administered care and therapeutics potentially affecting vitC bioavailabilty, the data suggest significant alterations in the pharmacokinetics of vitC in this group of patients, reflected by the discrepancy in the almost linear course of the plasma concentration curve opposed to the predicted increase over time. Whether reestablishing normal vitC status in critically ill patients has a significant clinical impact on disease prognosis remains to be established, but promising results are emerging [55][56] and controlled trials are under way. A very recent meta-analysis suggests that vitC therapy significantly shortens the stay of patients in the intensive care unit [57].
In diabetes, reduced levels of plasma vitC is reported in both insulin demanding and noninsulin demanding diabetic patients [58][59][60][61]. A prospective evaluation of older adults in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study cohort, indicate that the use of vitC supplementation may reduce the risk of diabetes, supporting further investigations and controlled trials to identify a putative relationship between vitC levels and diabetes [62]. Supplementation with vitC (500 mg/day) increased insulin sensitivity and the expression of the SVCT2 transporter in skeletal muscle in type 2 diabetic patients [63], supporting findings that an intake of high-dose ascorbic acid (above 1 mg/day) exerted a beneficial effect on maintaining blood sugar homeostasis and decreasing insulin resistance in type 2 diabetic patients [61]. In a randomized controlled cross-over study of type 2 diabetes patients, an intake of 500 mg vitC twice daily for four months significantly improved glucose homeostasis as well as decreased blood pressure compared to placebo treated controls, linking vitC supplement to improved blood-sugar balance and cardiovascular function [64]. Positive effects of vitC on vascular hallmarks linked to diabetes have previously been indicated; in young diabetes type 1 patients, poor vitC status was linked to increases in the arterial vascular wall, indicating a putatively increased risk of atherosclerotic disease in these patients [65]. In type 2 diabetic patients with coronary artery disease, a high-dose supplementation (2 mg/day) for 4 weeks reduced circulating markers of thrombosis, supporting a beneficial role of vitC on the vascular system [66]. Collectively, the above evidence suggests that a higher metabolic turnover of vitC in diabetes can be counter-balanced by supplementation. However, if it also improves the long-term prognosis remains to be evaluated.

3. Conclusion

In conclusion, the pharmacokinetics of vitC is complex, dose-dependent, and compartmentalized at physiological levels, while independent of dose and first order at pharmacological levels. VitC homeostasis is dependent on several genetic, socio-economic and lifestyle-associated factors and well as the health status of the individual. Unfortunately, the lack of integration of this fundamental knowledge has left deep traces of design flaws, misconceptions, misinterpretations, and erroneous conclusions in the scientific literature. To this day, these inherited problems continue to hamper our ability to properly evaluate the role of vitC in human health and its potential relevance in disease prevention and treatment. Therefore, the overtly exaggerated optimistic view that enough vitC can cure everything continues to battle the dismissive negligence of refusal to re-examine the literature based on our current knowledge. To realize the full potential of vitC in both health and disease, these two extremes need to converge towards common ground.

This entry is adapted from the peer-reviewed paper 10.3390/nu11102412

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