Vitamin C pharmacokinetics of plain and slow
release formulations in smokers
Michael Viscovicha, Jens Lykkesfeldtb, Henrik E. Poulsena,*
aDepartment of Clinical Pharmacology Q 7642, Rigshospitalet, Copenhagen University Hospital,
Blegdamsvej 9, DK-2100 Copenhagen, Denmark
bDepartment of Pharmacology and Pathobiology, Royal Veterinary and Agricultural University,
Received 13 October 2003; accepted 17 January 2004
Summary Background & aims: Combination of the antioxidants ascorbic acid in slow
release formulation and a-tocopherol can retard the progression of atherosclerosis.
In order to determine if differences in formulation could explain some of the
different results in the intervention trials we determined selected pharmacokinetics
for two different formulations of ascorbic acid together with a-tocopherol.
Methods: Single-blinded, randomised, placebo-controlled intervention study with
48 healthy men, aged 20–65 years, smoking X5 cigarettes/day. Subjects received
250mg plain release ascorbic acid and 91mg plain release d-a-tocopheryl acetate,
250mg slow release ascorbic acid and 91mg plain release d-a-tocopheryl acetate or
placebo twice daily for 4 weeks. A series of blood samples were collected after
administration of the first dose and repeated after 4 weeks of supplementation.
Results: The fluctuation of ascorbic acid plasma concentrations decreased
significantly (P ¼ 0:003) after 4 weeks supplementation in the slow versus the plain
Conclusions: This study shows that there were pharmacokinetic differences
between plain and slow release formulations of ascorbic acid. However, these
effects are small and unlikely to be of significant clinical importance.
& 2004 Elsevier Ltd. All rights reserved.
Vitamin C, or ascorbic acid, cannot be synthesised
by the human body.1Man therefore depends on
dietary intake to maintain vital biological functions
dependent on ascorbic acid. While it is well
accepted that ascorbic acid intake in doses of
about 20–90mg per day are sufficient to prevent
scurvy,2,3considerable controversy exists about the
effects of so-called mega doses, i.e. ‘‘gram’’ doses,
on the major diseases in the western society:
Cancer and atherosclerosis. A few small focused
trials4–6and larger preventive trials7of up to a few
years duration have shown benefits from antiox-
idant supplementation, e.g. reduction of the
atherosclerotic progression. These positive findings
from intervention studies are at variance with
larger and longer preventive trials where it was not
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*Corresponding author. Tel.: þ45-3545-7671; fax: þ45-3545-
E-mail address: firstname.lastname@example.org (H.E. Poulsen).
S0261-5614/$-see front matter & 2004 Elsevier Ltd. All rights reserved.
Clinical Nutrition (2004) 23, 1043–1050
possible to find positive effects of ascorbic acid in
combination with vitamin E and b-carotene.8–15
Recently, the antioxidant supplementation in
atherosclerosis prevention (ASAP) study showed a
beneficial effect on atherosclerotic progression of
ascorbic acid and a-tocopherol in combination using
a slow release formulation of ascorbic acid.4,5The
significant effect as shown by a reduced progression
of atherosclerosis was only seen for the smoking
male and no effect was found in female smokers as
well as non-smokers of both genders. Furthermore
the ASAP study did not show any effect with
ascorbic acid or a-tocopherol individually. The
rationale for using a slow formulation of ascorbic
acid was to reduce fluctuations in the plasma
concentrations of ascorbic acid. Earlier studies had
indicated that this was achieved after a single
dose.16However, more detailed pharmacokinetic
studies were not conducted and little is known
about the basic pharmacokinetics of ascorbic acid
in plain versus slow release formulation. The
bioavailability of ascorbic acid in non-smoking
men has been found to be dose-dependent and
doses exceeding 500mg are largely excreted or not
absorbed.17Another pharmacokinetic study did not
find any significant effect of smoking on the
bioavailability, maximum plasma concentration or
elimination for erythorbic acid, a stereo isomer of
To further investigate the mechanism that
retarded the progression of atherosclerosis in the
ASAP study, we have studied the possible pharma-
cokinetic differences between plain and slow
release ascorbic acid in smoking men and expanded
these studies to the steady state situation following
4 weeks of supplementation.
Materials and methods
Healthy men 20–65 years of age and smoking five or
more cigarettes per day were recruited from the
Copenhagen area by newspaper advertisements.
Exclusion criteria were uncontrolled hypertension
(diastolic blood pressure 4105mmHg), abnormal
430kgm?2), insulin dependent type 1 diabetes,
simultaneous participation in other clinical trials,
any condition limiting mobility, severe disease
shortening life expectancy or other disease or
condition worsening the adherence to the measure-
ments or treatment. Although no restrictions
regarding ethnicity were made, the study popula-
tion was exclusively Caucasian. A written informed
consent was obtained from all subjects. The
Independent Ethic Committee of the City of
Copenhagen approved the study protocol and the
study was conducted according to the Declaration
of Helsinki II and the guidelines of GCP with the
exception of external monitoring, as it was a single
site, small investigator initiated study. Sixty-six
men completed an in-house screening and 50 of
these men completed the first trial visit at the
Department of Clinical Pharmacology, Copenhagen
University Hospital in accordance with the study
protocol. Four weeks later 48 subjects completed
the second visit. Two volunteers dropped out
because of lack of time from newly acquired jobs.
The study was a single-blinded (study participants
only), single-site, randomised, placebo-controlled
intervention study with three treatment groups.
The supplementation comprised tablets of (A)
250mg plain release ascorbic acid and 91mg plain
release d-a-tocopheryl (as acetate corresponding
to 100mg), (B) 250mg slow release ascorbic acid
and 91mg plain release d-a-tocopheryl (CellaVies)
or (C) identical placebo tablets. Two tablets were
consumed daily, one with the morning meal and one
with the evening meal. The trial period was 4
weeks, where steady state for ascorbic acid2,19–21
and a-tocopherol is achieved.22,23The supplements
were generously donated by Ferrosan A/S (Den-
mark) and contained by analysis 267mg ascorbic
acid and 104mg d-a-tocopheryl acetate. The doses
of the supplements were identical to the doses
used in the ASAP study.4,5Subjects were advised to
stop supplement of vitamins and natural remedies
containing antioxidants as soon as a written
informed consent was obtained at the screening
visit. Compliance with trial treatment was calcu-
lated by counting any remaining tablets at the
second trial visit.
Twenty subjects from each supplement group were
invited to stay for a 12h pharmacokinetic study to
test the absorption and distribution of ascorbic acid
and a-tocopherol. The first blood sample (baseline)
was drawn after overnight fasting. After adminis-
tration of the supplement, twelve blood samples
were drawn over the next 12h with 45min interval
between the first nine samples and prolonged time
interval for the last drawn blood samples. A diet
with negligible ascorbic acid content was provided
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1044 M. Viscovich et al.
during the pharmacokinetic sampling period. The
pharmacokinetic study was repeated after a 4-
week supplementation period with plain or slow
release formulation. Nineteen subjects completed
the second trial visit from each supplement group.
To determine a possible seasonal variation, a
placebo group consisting of ten subjects was
included. We have previously shown that plasma
ascorbic acid does not fluctuate among the placebo
and consequently no pharmacokinetic
evaluation was conducted for this group.
Measurements of antioxidants
Blood samples were drawn from an indwelling
venflon catheter in a forearm vein into pre-cooled
evacuated tubes containing 5ml anticoagulant Li-
heparin (Beckton Dickinson). The vacutainer was
2000?g (41C). All standards were from Fluka
Aliquot (500ml) of plasma was immediately
stabilized with an equal amount cold (10%) meta-
phosphoric acid containing 2mM EDTA. The pre-
cipitate was removed by centrifugation (1min at
16,000?g). The supernatant was stored at ?801C
for less than one month until analysis. It has
previously been shown that ascorbic acid is stable
under these conditions.24Total plasma ascorbic
acid (i.e. ascorbic acidþdehydroascorbic acid) was
separated by reverse-phase ion-pairing high-per-
formance liquid chromatography (HPLC) and quan-
elsewhere.25Four observations were missing and
were replaced after the following principle: if the
first observation was missing; it was replaced by the
last observation. Other missing observations were
replaced by the preceding observation.
a-Tocopherol and g-tocopherol were measured as
reversed-phase HPLC assay with electrochemical
detection were specifically optimised for the
separation of a- and g-tocopherol.27The concen-
trations reported for g-tocopherol also include
those for b-tocopherol, which does not separate
from the former under reverse-phase conditions
but represents less than 10% of the two forms in
for twominutes at
The conditions for the
Pharmacokinetic parameters were determined by
using WinNonlin software version 2.1 (Scientific
Consulting, Inc.). A non-compartmental model type
was used in combination with a linear/log trape-
zoidal calculation method. The area under the
plasma concentration curve (AUC) was calculated
from zero to the last observation. Data were
further analysed by using Statistica version 6
(StatSoft, Tulsa, OK). Differences between plain
release, slow release and placebo groups were
analysed with one-way ANOVA. t-Test for indepen-
dent samples by groups was used to examine the
difference between the plain and slow release
formulations while effects of supplementations
tested by using the t-test for dependent samples
by groups. A two-tailed P value o0.05 was
considered statistically significant.
The study start characteristics of the population
are summarized in Table 1. There were no
significant differences in the subjects’ character-
istics between the groups, except for lower
compliance (tablet count) in the placebo group
(Po0:001). When comparing compliance for the
plain and slow release groups, no significant
differences were observed.
Changes in ascorbic acid plasma concentrations
are illustrated in Fig. 1 and Table 2. At study start,
no significant differences in plasma ascorbic acid
concentrations were observed between groups.
After ingestion of a plain release tablet plasma
74.2724.3mmol/l at 4.0h (Tmax). Tmax for the
slow release group was 5.0h and the plasma
concentration increased 38% (Po0:001) to reach
maximum concentration (Cmax) corresponding to
70.2718.3mmol/l (Po0:05). No significant differ-
ence was observed in the span (maximum concen-
tration subtracted the minimum concentration)
between the groups. Furthermore, there was no
difference in AUC between the groups.
After 4 weeks of supplementation, plasma
82.4714.6mmol/l for plain and slow release group,
respectively. The plasma concentration in the
placebo group decreased to 39.0717.9mmol/l.
There was a significant difference (Po0:001) in
the trough ascorbic acid concentration between
the groups receiving supplements and placebo,
while no difference was found between the plain
and slow release groups. At the second visit, the
ascorbic acid concentration increased more mod-
erately; 26% (Po0:001) (96.9718.4mmol/l at Tmax
ARTICLE IN PRESS
Vitamin C pharmacokinetics1045
2.1h; plain release) and 11% (Po0:001) (91.67
13.6mmol/l at Tmaxof 2.4h; slow release), respec-
tively. The Cmaxwas higher in the plain compared to
the slow release group and a significant difference
for the span between the two groups was observed
Effect of supplementation
Four weeks of supplementation resulted in signifi-
cantly increased plasma concentrations of ascorbic
acid for both plain and slow release formulations
(Po0:001; Table 2). The ascorbic acid concentra-
(Po0:001). A decrease in Tmaxof about 30% could
be observed in both the plain and slow release
groups (Po0:01). Moreover, AUC increased 66%
and 42% in the plain and slow release groups,
respectively, after 4 weeks of supplementation
(Po0:001). The maximum ascorbic acid plasma
concentration (Cmax) also increased significantly in
both supplemented groups (Po0:01). There was no
significant change in the span from study start to
after the 4 weeks supplementation period for the
two active treatment groups.
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02468 10 12
Plasma ascorbic acid (µM)
Figure 1 Plasma ascorbic acid concentration. Changes in plasma ascorbic acid concentration after intake of one tablet
of plain release ascorbic acid (250mg) and plain release a-tocopherol (91mg) (plain release) or slow release ascorbic
acid (250mg) and plain release a-tocopherol (91mg) (slow release) at study start (closed circles and squares,
respectively) and after 4 weeks of supplementation (open circles and squares, respectively). Error bars are SEM.
Characteristics of subjects. Characteristics of the subjects for the plain release, slow release and the
Characteristic Plain release (n ¼ 19) Slow release (n ¼ 19)Placebo (n ¼ 10)
Mean SDMean SD MeanSD
Body mass index (kgm2)
Pack year (yr, smoking 1 pack/d)
Wash out period (d)
Trial period (d)
***Po0:001 by one-way ANOVA test for plain release vs. slow release vs. placebo.
1046M. Viscovich et al.
When analysing the plasma a-tocopherol concen-
tration for the first ten subjects (six subjects
receiving plain release and four receiving slow
release), no absorption, distribution or elimination
could be observed within the 12h of blood sampling
from either visits (data not shown). Therefore, it
was decided to analyse only the baseline samples of
The mean study start concentrations of a-
tocopherol and g-tocopherol were similar in all
groups. After 4 weeks of supplementation, a-
tocopherol concentration increased 32% (plain
release) and 25% (slow release) (Po0:001). During
the same period the concentration in the placebo
group decreased 24% (Po0:001). In contrast, the g-
tocopherol concentration decreased 69% after 4
weeks of supplementation with plain release
tablets, 81% for subjects receiving slow release
tablets and 42% for controls. The g-tocopherol
concentration was significant different for the plain
release versus slow release group (Po0:01). After 4
weeks of supplementation, a several-fold increase
in the a-/g-tocopherol plasma ratio was found in
both supplemented groups, while a smaller in-
crease was observed in the placebo group.
Plasma ratios for ascorbic acid and a-tocopherol
were also examined (data not shown). Neither at
study start nor after 4 weeks of supplementation a
significant difference was observed for the plain
and slow release groups versus placebo. There was
no difference between the two supplemented
The possible beneficial effects of antioxidant
supplementation continue to be subject to much
debate. Most preventive trials and a meta-analysis
of randomised trials have not found a benefit of
antioxidant supplementation,8–15while a few smal-
ler and more focused trials investigating people
with pre-existing vascular disease such as the ASAP
study4,5have found significant beneficial effects. In
most preventive trials where ascorbic acid was used
as supplement, ascorbic acid was formulated as
plain release. In contrast, the ASAP study used
ascorbic acid in a slow release formulation. Thus,
we wanted to investigate if the above discrepancy
could relate to pharmacokinetic differences from
different formulations of ascorbic acid.
In the present study, we examined the pharma-
cokinetics of the vitamin supplement used in the
ASAP study (slow release formulation) and com-
pared them with those of a similar plain release
supplement and placebo. A larger span in plasma
ascorbic acid concentration for the plain versus
slow release group was expected.
After 4 weeks of supplementation with the slow
release formulation, fluctuations in plasma ascor-
bic acid were below those found in the plain
ARTICLE IN PRESS
tocopherol and g-tocopherol for the plain release, slow release and the placebo group.
Plasma concentrations at study start and after 4 weeks. Plasma concentration of ascorbic acid, a-
(n ¼ 19)
(n ¼ 19)
(n ¼ 10)
P (t-test for
SD Plain vs.
*Po0:05;**Po0:01;***Po0:001 by t-test for dependent samples for study start vs. 4-weeks.
Vitamin C pharmacokinetics1047
release group. This finding is in agreement with an
earlier smaller study.16However, we found no
difference in Tmax for the plain release group
versus the slow release group after intake of the
first tablet. After 4 weeks of supplementation a
steady state was reached23,29and Tmax decreased
approximately 30% in both supplemented groups
compared to study start. Such findings have been
reported earlier,16,29but no previous reported
mechanism for the Tmax decrease has been sug-
gested. During the 12h pharmacokinetic studies,
the AUC and Cmax values of ascorbic acid did not
differ significantly between the two supplemented
groups, neither at study start nor after 4 weeks of
supplementation (Table 3).
This coherence was also found by Nyyssonen
et al.,16while disagreement has been expressed in
the area with respect to pharmacokinetic differ-
ences for the slow versus plain release formulation.
One study observed higher AUC and Cmax values
after the first dose in film-coated tablets compared
with an enteric-coated pellet preparation, while at
steady state the AUC and Cmaxvalues were higher in
the enteric-coated pellet preparation.30In agree-
ment, other studies found a higher AUC in slow
release tablets versus plain release tablets,29,31but
higher AUC for plain release forms versus slow
release forms have also been observed.32
As expected, 4 weeks supplementation with
ascorbic acid and a-tocopheryl acetate increased
the plasma concentrations of ascorbic acid and a-
tocopherol significantly. In contrast, decreased
ascorbic acid and a-tocopherol plasma concentra-
tions were observed for the placebo group. Due to a
general misconception, subjects commonly avoided
fruits and vegetables rather than continuing with
their normal diet as planned. This phenomenon was
presumably equally distributed among all groups.
Previous work showed that a- and g-tocopherol are
taken up without preference by the intestine and
secreted in the chylomicron particles.33,34The
chylomicron remnants, which are not transported
and transferred to peripheral tissues,35are subse-
quently taken up by the liver. The liver has a
preference for incorporating RRR-a-tocopherol into
lipoproteins in plasma through the specific a-
creases the incorporation of g-tocopherol into
lipoproteins and increases the excretion of g-
tocopherol through the liver. In the present study,
we also found that the plasma concentration of g-
tocopherol decreased more for subjects receiving
the slow release dosage form of ascorbic acid
compared with the plain release.
In conclusion, we found significant differences in
fluctuation of plasma ascorbic acid when supple-
mented as a plain or slow release formulation,
respectively, in combination with a-tocopherol.
However, the authors find it unlikely that the
relative small differences observed between these
two formulations be of major clinical importance.
We are indebted to Lis Kjær Hansen, Jytte Jensen,
Bodil Mathiasen, Benedikte Bukhave, Annie B.
Kristensen and Jytte Nielsen for their excellent
ARTICLE IN PRESS
4 weeks of supplementation with plain or slow release tablet.
Pharmacokinetic parameters at study start and after 4 weeks. Pharmacokinetics at study start and after
(n ¼ 19)
(n ¼ 19)
P (t-test for
Mean SDn MeanSDn Plain vs. slow
5.0 2.5 18
*Po0:05;**Po0:01;***Po0:001 by t-test for dependent samples for study start vs. 4-weeks.
1048M. Viscovich et al.
Medical Research Council, Ferrosan A/S and BAT
supported this work.
and technical assistance. The Danish
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