**4. Pharmacokinetic Bioavailability Studies in Humans**

Pharmacokinetic studies show transient changes in plasma vitamin C levels and urinary excretion over the hours following ingestion of the vitamin C-containing test substance (relevant studies are shown in Table 3). Supplemental vitamin C typically takes about two hours to reach maximal plasma levels following ingestion. An early animal study found that vitamin C provided in citrus fruit media took longer to reach peak plasma concentrations compared with a synthetic vitamin C solution and also provided a larger area under the plasma vitamin C concentration-time curve [65]. These same investigators observed a comparable trend in human subjects supplemented with 500 mg vitamin C in the presence or absence of a citrus fruit extract [81]. The citrus fruit extract delayed maximal plasma levels by one hour and provided a 35% increase in vitamin C bioavailability. Interestingly, the citrus fruit extract increased 24 h urinary vitamin C excretion in participants pre-saturated with vitamin C, but decreased excretion in non-saturated participants compared with synthetic vitamin C alone. This suggests that the baseline vitamin C status of the individual may affect the comparative bioavailability of vitamin C. Although two other studies showed increased urinary excretion in vitamin C pre-saturated subjects in the presence of fruit juice [71,82], another pre-saturation study showed comparable plasma levels and 24 h urinary excretion in the presence of mixed bioflavonoids [83]. It should be noted that doses of 500 mg vitamin C have reduced intestinal bioavailability [78] and are significantly higher than would be obtained through a normal daily diet.

A number of pharmacokinetic studies have shown comparable bioavailability of vitamin C supplied in synthetic form or in the presence of foods or fruit juices [84–88]. Nelson *et al.* [88] used an intestinal triple lumen tube perfusion model to investigate the absorption of synthetic vitamin C and that from an orange juice solution. This method allows direct measurement of intraluminal events and showed no difference in the absorption of vitamin C from the two test solutions. A few pharmacokinetic studies have shown transient decreases in plasma vitamin C levels and/or urinary excretion at specific time points in the presence of food and fruit juices [34,71,84,85]. The physiological relevance of these transient differences is, however, likely minimal.

We recently carried out a pharmacokinetic bioavailability study of synthetic *versus* kiwifruit-derived vitamin C in nine non-smoking males (aged 18–35 years) who had "healthy" or "optimal" (*i.e.*, >50 μmol/L) baseline levels of plasma vitamin C [89]. The participants received either a chewable tablet (200 mg vitamin C) or the equivalent dose from gold kiwifruit. Fasting blood and urine were collected half hourly to hourly over the eight hours following intervention. Plasma ascorbate levels increased from 0.5 h post intervention, although no significant differences in the plasma time-concentration curves were observed between the two interventions. An estimate of the total increase in plasma ascorbate indicated complete uptake of the ingested vitamin C tablet and kiwifruit-derived vitamin C. There was an increase in urinary ascorbate excretion, relative to urinary creatinine, from two hours post intervention. There was also a significant difference between the two interventions, with enhanced ascorbate excretion observed in the kiwifruit group. Urinary excretion was calculated as ~40% and ~50% of the ingested dose from the vitamin C tablet and kiwifruit arms, respectively. Overall, our pharmacokinetic study showed comparable relative bioavailability of kiwifruit-derived vitamin C and synthetic vitamin C [89].

