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Blanchard J, Tozer TN & Rowland M: Pharmacokinetic perspectives on megadoses of ascorbic acid. Am. J. Clin. Nutr. 66, 1165-1171

Authors:

Abstract

Ascorbic acid (vitamin C) is commonly used as a dietary supplement, often in megadoses. However, as the daily oral dose is increased, the concentration of ascorbic acid in the plasma and other body fluids does not increase proportionally, but instead tends to approach an upper limit. For example, when the daily dose is increased from 200 to 2500 mg (from 1.1 to 14.2 mmol) the mean steady state plasma concentration increases only from approximately 12 to 15 mg/L (from 68.1 to 85.2 mumol/L). Published data were reanalyzed with an integrated modeling approach to shed new quantitative light on this phenomenon. This analysis is based on the renal clearance of ascorbic acid, which rises sharply with increasing plasma concentrations as a result of saturable tubular reabsorption. The analysis indicates that both saturable gastrointestinal absorption and nonlinear renal clearance act additively to produce the ceiling effect in plasma concentrations. As a consequence of this ceiling effect, there is no pharmacokinetic justification for the use of megadoses of ascorbic acid.
ABSTRACT Ascorbic acid (vitamin C) is commonly used as
a dietary supplement, often in megadoses. However, as the daily
oral dose is increased, the concentration of ascorbic acid in the
plasma and other body fluids does not increase proportionally, but
instead tends to approach an upper limit. For example, when the
daily dose is increased from 200 to 2500 mg (from 1.1 to 14.2
mmol) the mean steady state plasma concentration increases only
from “¿@l2to 15 mg/L (from 68.1 to 85.2 @moIIL).Published data
were reanalyzed with an integrated modeling approach to shed
new quantitative light on this phenomenon. This analysis is based
on the renal clearance of ascorbic acid, which rises sharply with
increasing plasma concentrations as a result of saturable tubular
reabsorption. The analysis indicates that both saturable gastroin
testinal absorption and nonlinear renal clearance act additively to
produce the ceiling effect in plasma concentrations. As a conse
quence of this ceiling effect, there is no pharmacokinetic justifi
cation for the use of megadoses of ascorbic acid. Am J Clin
Nutr l997;66:l 165—71.
KEY WORDS Ascorbic acid, vitamin C, pharmacokinet
ics, megadosing, renal clearance, bioavailability
INTRODUCTION
Over the past few decades a wide variety of reasons for
supplementing the diet with ascorbic acid and other antioxidant
vitamins have been proposed. These include the prevention of
cancer, heart disease, and cataracts (1). The antioxidant vita
mins have been highly promoted in the lay press and by
vitamin manufacturers, with the result that @20million people
in the United States take daily supplements of ascorbic acid (2),
making it the most commonly supplemented vitamin (3). Many
people believe that the water solubility of ascorbic acid permits
it to be ingested in very large (mega) doses without any toxic
effects. A megadose has been defined (4) as a dose 10 times
the US recommended dietary allowance (RDA), which is cur
rently 60 mg (0.34 mmol) (5). Hence, a megadose is 600 mg
(3.4 mmol). Vitamins taken in excess of the body's needs can
have undesirable effects. A recent report indicated that supple
mentation with megadoses of ascorbic acid may actually pose
a significant risk to health (6).
On the basis of these concerns it seems prudent to establish
the dose of ascorbic acid necessary to maintain and promote
good health. The purpose of this report is not to debate the
possible health-related merits of increasing the dose of ascorbic
acid above the current US RDA, but rather to focus on the
effect of ascorbic acid pharmacokinetics on the use of mega
doses. The term pharmacokinetics as used here refers to the
kinetic aspects of absorption and elimination (metabolism and
renal excretion). The interplay of these two opposing processes
determines the amount of ascorbic acid in the body.
To quantify the relation between dosing and plasma concen
tration, a model is needed. Determination of the appropriate
model for ascorbic acid has been particularly difficult because
of saturability in both absorption and elimination (7—13). Renal
clearance (CLR) exhibits the most nonlinear behavior of all
kinetic parameters, yet is the most readily quantifiable. Fur
thermore, renal excretion is the major elimination pathway at
high doses. This report reexamines the kinetics of ascorbic acid
in humans from this perspective by using a novel approach and
makes some conclusions relevant to the rational dosing of
ascorbic acid. Literature data from several sources are com
bined to show trends and to test predicted outcomes. Because
of the multiple sources of these observations, parameter values
should be considered as approximations.
ANALYSIS OF DATA FROM THE LITERATURE
The relation between CL@ and the plasma concentration of
ascorbic acid is illustrated in Figure 1, a compilation of data
from several sources. Ralli et al (9) summarized the relation
between CLR and plasma concentration at steady state (CS) for
ascorbic acid by using a model developed for glucose (14, 15)
(see Appendix A). The model of Ralli et al (9) fit the obser
vations well at higher concentrations (> 8 mg/L, or > 45.4
p@mol/L) but did not predict the virtually zero CLR at low
ascorbic acid concentrations (< 8 mgIL, or < 45.4 @molIL). In
fact, this simulation produced a y intercept of 3.1 Lid. Subtrac
tion of the y-intercept value from all other values of CL@
yielded a corrected CLR that was used to generate the solid line
shown in Figure 1. The function represented by this line
becomes the model for the expected relation between CL@and
I From the Department of Pharmacology and Toxicology, College of
Pharmacy, University of Arizona, Tucson; the Department of Biopharma
ceutical Sciences, School of Pharmacy, University of California, San
Francisco; and the School of Pharmacy and Pharmaceutical Sciences,
University of Manchester, Manchester, United Kingdom.
2 Address reprint requests to J Blanchard, Department of Pharmacology
and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
85721. E-mail: BLANCHRD@tonic.pharm.arizona.edu.
Received January 29, 1997.
Accepted for publication May 22, 1997.
1165Am J Clin Nutr 1997;66:1165—7l. Printed in USA. tO 1997 American Society for Clinical Nutrition
Pharmacokineticperspectiveson megadosesof ascorbic
James Blanchard, Thomas N Tozer, and Malcolm Rowland
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BLANCHARD ET AL
With regular (continuous) dosing, a steady state of ascorbic
acid is reached in the body when the daily rate of absorption is
equal to the daily rate of elimination. The rate of elimination
(and hence absorption) is obtained as the product of the plasma
concentration (CSS)and the total clearance by all processes of
elimination (CLx). To estimate the relation between the plasma
concentration of ascorbic acid and the daily dosing rate (mg/d),
total clearance is therefore needed (see Eq A7 in Appendix A).
Total clearance is the sum of CLR and nonrenal clearance
(CLNR). The latter is primarily associated with metabolism of
ascorbic acid to dehydroascorbic acid, 2,3-diketogulonic acid,
oxalate, and ascorbate-2-sulfate (13, 16) and, at doses > 180
mg (> 1.0 mmol), carbon dioxide (17).
At plasma concentrations < 6—8mg/L (< 34.1—45.4 @moV
L), corresponding to daily dosing rates of 0—100mg/d (0—0.6
mmol/d), renal excretion is virtually nil (7, 8). This permits an
estimate of CL@ to be calculated as the reciprocal of the slope
of a plot of the CSSversus daily oral dosing rate (see Eq A9 in
Appendix A). The value of CL@ obtained from the data shown
in Figure 5 of reference 7 is “¿@‘7.5L/d and is assumed to remain
constant over the range of doses examined. Although nonrenal
(metabolic) clearance may decrease as the dose is increased
into the megadose range, no data appear to be available to test
this possibility. Furthermore, the assumption of constancy of
CL@ in the megadose range is not critical because it becomes
a minor component of CL,... At any plasma concentration, a
corresponding CL,. of ascorbic acid can be calculated, which
increases from 7.5 L/d (CLNR) to 180 Lid (CL1@@@plus 173
Lid, the maximum value for CLV; Figure 1A), as the plasma
concentration increases. Once CL,. is known, the daily oral
dose needed to maintain a steady state plasma concentration
can be calculated, ie, CL,- X CSS, assuming complete ab
sorption. The predicted relation is shown as the solid line in
Figure 2.
The observedplasma concentrations obtained from several
different literature sources appear to be reasonably well pre
dicted by the model up to daily doses of 100—200mg (0.6—1.1
mmol). The overprediction at daily doses > 200 mg (> 1.1
mmol) is most likely the result of incomplete absorption of
administered ascorbic acid. As mentioned earlier, at steady
state, the rate of elimination (CLi. X CSS)is equal to the rate of
absorption. Consequently, the ratio of the rate of absorption to
the rate of administration (dose/d), commonly referred to as
bioavailability (F) can be calculated (see Eq A7 in Appendix
A). The bioavailability values calculated for the mean plasma
concentrations observed in reference 8 at daily doses of 200,
400, 1000, and 2500 mg (1.1, 2.3, 5.7, and 14.2 mmol) are
shown in Table 1. Additional values can be estimated from the
observed (12) plasma concentrations of 15.4 mgfL (87.4
@amol/L)and 19.5 mgfL (110.7 @tmolIL)seen at daily doses of
1—3g (5.7—17.0mmol) and 8—12g (45.4—68.1mmol), respec
tively. Calculated fractions absorbed (bioavailability) for the
various doses are shown in Figure 3.
The calculated fraction excreted unchanged, equal to CLR/
(CLR + CL@), and that determined experimentally from the
oral administration of [‘4C]ascorbicacid are listed in Table 2
(13). The assumptions made in using urinary radioactivity
measurements are that the vitamin is not decomposed in the
gastrointestinal tract, or that metabolites formed there are not
excreted in the urine, and that all labeled ascorbic acid metab
olites produced systemically are completely excreted into the
A
200
I
200
p100.
@ 50@
0
S
I
50
0
0 500 1000
1500
300
FIGURE 1. (A) Renalclearanceof ascorbicacid as a functionof its
plasma concentration. Data are obtained from three sources: •¿,reference
9 [Figure2, intravenousdosesof 1500—6000mg (8.5—34.1mmol)were
usedj; 0, reference 10 (Figure 4); and @,reference 7 (Figure 6). The renal
clearance in Figure 2 of reference 9 is expressed as the ratio of clearances
of ascorbic acid and inulin, the latter being a measure of glomerular
filtration rate. Because the subjects were probably young, healthy, male
volunteers, the actual renal clearance was estimated by using an inulin
clearance of 173 LId. The renal clearance values from reference 7 were
calculated from the excretion rate and concentration data provided in
Figure 6. The line is the prediction from a model for renal excretion (see
text).(B)Theobservedrenalclearancevaluesintheconcentrationrangeof
0-SO mg/L (0-283.9 @mol/L).
plasma concentration. The most notable features of Figure 1
are a virtual lack of CLR at low plasma concentrations (< 8
mg/L, or < 45.4 @moLfL),values that approach the glomerular
filtration rate (173 LId) at very high plasma concentrations
(> 100 mgfL, or > 567.8 @molIL),and a sharp change in CLR
in the plasma concentration range of from 10 to 30 mg/L (from
56.8 to 170.3 @imolIL).
Plasma concentration (p@molIL)
B
150 -
0 100 200
Plasma concentration (pmolIL)
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PHARMACOKINETICS OF ASCORBIC ACID MEGADOSES
1167
200@
150@
ability to decrease with increasing dose is clearly evident from
the literature values cited. However, the magnitudes of the
bioavailability values reported in the literature for daily doses
> 200 mg (1.1 mmol) are considerably greater than the values
calculated here. One likely reason for this discrepancy is that
bioavailability is commonly calculated from the ratio of the
area under the oral plasma concentration versus time curve to
the intravenous concentration versus time curve (AUC), as
suming that the AUC is directly proportional to the amount
absorbed, which implies constancy of clearance. As shown in
Figure 1, the CLR of ascorbic acid increases sharply above a
threshold plasma concentration of ‘¿@@‘8—10mg/L (45.4—56.8
j@mol/L). As shown by Levine et al (8) and others, plasma
tendency for a ceiling in the plasma concentration of ascorbic acid
at doses between 200 mg and 10 g (1.1 and 56.8 mmol) is largely
due to the limited capacity for absorption (Table 1),probably as a
result of a saturable transport mechanism (20, 21). Further clan
fication of the relative contributions of the various components of
ascorbic acid pharmacokinetics to the ceiling effect will require
more Critical attention to study design and data analysis in future
studies.
The metabolism of ascorbic acid has been reported to be
saturable (22). This conclusion comes from the observation of
an upper limit to the rate of excretion of ascorbic acid metab
olites as the oral dose of ascorbic acid is increased (13).
However, the plasma ascorbic acid concentration also ap
proaches a ceiling as shown in Figure 2. Reanalysis of the
relation between the metabolite excretion rate and plasma
ascorbic acid concentration reported by Kallner et al (13)
indicates that this ratio remains essentially constant and that
there is no saturation of ascorbic acid metabolism.
An additional consideration is the effect of the administra
tion of ascorbic acid in divided daily doses, in solution, or with
food or water on the fraction of the dose absorbed. Because
ascorbic acid absorption is mediated by transport sites in the
proximal small intestine (20, 21), factors that reduce the rate at
which the concentration of ascorbic acid builds up at these
carrier sites (eg, a delay in the rate of stomach emptying) would
be expected to increase the fraction absorbed. Indeed, the
F
-I-
-r
a
-I-
50@
concentrations are considerably higher soon after intravenous
dosing than after oral dosing. Consequently, CLR of ascorbic
acid would be greater after intravenous dosing than after an
equivalent oral dose. The result is that a direct comparison of
0 500 1000 1500 2000 2500 an oral AUC with an intravenousAUC produces an overesti
mate of bioavailability. Unfortunately, there is no simple
method to account for nonlinear renal tubular reabsorption and
no method for estimating the oral bioavailability of ascorbic
acid is ideal.
The bioavailability estimates reported here may be somewhat
biased because they are based on the assumption that the rate of
ascorbic acid absorption is constant. However, multiple oral doses
are expectedto producefluctuationsin the absorptionrate, and
consequently in plasma concentrations, at steady state. Although
in practicethese fluctuationsare not great the sharp change in
CLR with plasma concentrations of 10—30mgfL (56.8—170.3
pznoVL) produces a difference between the measured concentra
tion, usually obtained just before the next dose, and that expected
with a constant rate of ascorbic acid absorption. This results in an
underestimate of bioavailability. The true value probably lies
between the two estimates. Notwithstanding the uncertainty in the
estimate of bioavailability,the analysis does suggest that the
0
Daily dose (mg)
FIGURE 2. Model prediction (solid line) of the relation between
plasma ascorbic acid concentration at steady state and the daily dose
administered (assuming complete absorption). Observations are from four
sources: S, reference 8 (Figure ic); •¿,reference 12; 0, reference 7 (Figure
5); and A, reference 11.The data from references 8 and 12are the means ±
SDs of 6—11subjects. The remaining points represent values for individual
subjects. Note the substantial overprediction at doses > 200 mg (1.1
mmol).
urine. The radioactivity as ascorbic acid compared with total
radioactivity is then a measure of the fraction excreted un
changed. The agreement between the calculated and observed
values is excellent, lending further support to our assumption
that CL@ remains constant.
The contribution of metabolism and excretion to total elim
ination can be estimated from the component parts (CLx and
CL@) of the model for total clearance. The calculated rates of
these processes as a function of the plasma concentration are
shown in Figure 4. The graph illustrates how saturable renal
tubular reabsorption affects the contributions of the excretory
and metabolic pathways.
Consideration must be given to the saturable aspects of both
gastrointestinal absorption and renal tubular reabsorption. How
the steady state plasma concentration of ascorbic acid is pre
dicted to change with diminished renal function (from 100% to
10% of normal) as the daily oral dosing rate of the vitamin
increases is shown in Figure 5. Because of the sharply rising
CL@ with increasing plasma concentration, the plasma concen
tration rises, at most, by only “¿@‘50%for a 10-fold decrease in
renal function for daily doses up to @lg (5.7 mmol) (Figure
SA). However, higher dosing rates may be of concern because
the model predicts steady state concentrations > 40 mg/L
(227. 1 @mo1IL)at daily doses of@ 10 g (56.8 mmol) in
subjects with renal function that is 10% of normal (Figure
SB).
DISCUSSION
Our calculated values for bioavailability and the values re
ported in the literature from use of urinary recovery and other
methods are compared in Table 1. The tendency for bioavail
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Dose
‘¿
(mg/d).
. .
BiologicalfluidsampledPercentage
of dose
absorbed (reference)Percentage
of dose absorbed
2
(present study)Amount
of dose absorbed
(presentstudy)%%mg90—180Urine80—90(18)=10090—180200Blood112(8)79(8)158400Blood—45(8)180500Blood73(8)——1000Urine75(19)23(8)2301250Blood49(8)——1500Blood49.5(11)——2000Urine44.0
(19)17
(12)3402500Blood—13
(8)3253000Blood,
urine36.2(11); 39.1(19)——4000Urine27.5
(19)——5000Urine20.9
(19)——6000Blood25.6(11)——10000Blood—8(12)80012000Blood16.1(11)——
Daily dose (mg)'Fraction
excretedunchangedObserved2Calculated3300.070.10600.200.20900.340.291800.620.49200—0.52400—0.7010000.820.8420000.880.90
1168
BLANCHARD ET AL
TABLE 1
Effectof doseon theoralabsorptionof ascorbicacid
‘¿mg ascorbic acid/176.12 = mmol ascorbic acid.
2 Values are approximations calculated by using the model developed here and the steady state plasma concentrations reported in the references cited
in parentheses.
bioavailability of ascorbic acid was increased when given in
divided doses or concurrently with food (23).
Ingestion of sufficient ascorbic acid has health benefits, the
prevention of scurvy being the most obvious. A problem anses
in attempting to determine the most appropriate dose to main
tamandpromotegoodhealth.TheUSRDAof 60mg(0.3
mmol)/d is based on the average amount of the vitamin nec
essary to prevent the onset of scurvy with a sufficient margin
of safety to satisfy the needsof almost all healthy individuals
in the population. However, this amount of ascorbic acid has
been considered by some to be inadequate to maintain an
optimal body pool for all of the reactions in which ascorbic
acid participates (24). if maintenance of an optimum body pool
is the goal of vitamin supplementation, then the question anses
regarding what constitutes an optimum body pool and the daily
amount of nutrient needed to maintain it.
The RDA target body pool size is 1500 mg (8.5 mmol) (18).
It is around this level that radioactively labeled ascorbic acid
begins to appear in the urine (19). Although there is good
evidence that plasma concentrations of ascorbic acid tend to
reach a plateau of@ 12—15mgfL (68.1—85.2 @mol/L)as the
ascorbic acid dose is increased, higher doses could nevertheless
expand the ascorbic acid body pool and thereby lead to optimal
health (25) with respect to this important nutrient. Evidence in
opposition to this argument is provided by Jacob et al (26), who
reported that the body pool of ascorbic acid approaches an
upper limit of @20mg (0. 1 mmol)/kg body wt. This can be
achieved with an average intake of@ 138 mg (0.8 mmol)/d.
TABLE 2
Observed and calculated fraction excreted unchanged for various oral
doses of ascorbic acid
1.0
‘¿mg ascorbic acid/l76.12 mmol ascorbic acid.
2 Determined from the fraction of total urinary radioactivity associated
with unchanged ascorbic acid after oral administration of [‘4C]ascorbic
acid together with unlabeled vitamin (13).
3 Calculated from the ratio of CL,@/CL@@-, based on model predictions,
where CL@is renal clearance and CL,- is total clearance.
100 1000 10 000
p@
I.'
!@I0.6
Daily dose (mg)
FIGURE 3. Calculatedfractionof the administereddoseabsorbedfor
the oral daily doses shown in Figure 2 on the basis of data from references
8 (solid line) and 12 (dashed line).
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PHARMACOKINETICS OF ASCORBIC ACID MEGADOSES
1169
1.00
0.75
0.50
0.25
A
10%
S
S
S
Ii
P
S
S
.4
II
II
S
S
S
.4
S
S
.4
S
S
S
S
S
0 2500 5000 7500 10000
0
0 50 100 150
250
Plasma ascorbic acid
concentration (panol/L)
FIGURE 4. Schematic representation of the rates of metabolism (——¿—¿)
andexcretion(—) relativeto the totalrateof eliminationas a function
of the plasma concentration. For this simulation, metabolic clearance is
assumedto be constant(7.5Lid)at allconcentrations.
This results in an average steady state plasma concentration of
10 mgfL (56.8 @mol/L)in healthy, nonsmoking young adult
males.
if the goal is to keep the tissues at their upper limit then one
might ask whether there is any harm in taking doses vastly
larger than the US RDA. Evidence for and against the safety of
ascorbic acid megadoses can be found in the literature. For
example, Omaye et al (27, 28) defined a toxic dose as 500 mg
(2.8 mmol) to 10 g (56.8 mmol) and stated that toxic symptoms
including nausea, diarrhea, gastrointestinal disturbances, flatus,
stone formation, decreased copper absorption, and increased
dependency (ie, rebound scurvy) can be observed after inges
tion of ascorbic acid at these doses. Other reported adverse
effects due to ascorbic acid ingestion were summarized re
cently by Meyers et al (22). On the other hand, Bendich and
Langseth (29) listed studies in which doses of up to 10 g (56.8
mmol) were taken for 468 d without any reported side effects.
Most of the reported toxic effects are gastrointestinal in nature.
This is consistent with the fact that systemic exposure is not
increased greatly with dose, as the model reported here
predicts.
Although the appearance of toxicity in the megadose range is
controversial, the pharmacokinetic behavior of the vitamin
indicates that there is a negligible increase in plasma concen
trations when the oral daily dose is increased above @‘¿200mg
(1.1 mmol). The plasma concentration at steady state ap
proaches an upper limit at this and higher daily doses. The
relative constancy of the steady state plasma concentration at
daily oral doses above @200mg (1.1 mmol)/d is illustrated in
Figure 2. In the dosing range of200-2500 mg (1.1—14.2mmol),
the steady state plasma concentration increases only from 12
to 15mgIL (68.1 to 85.2 p@mol/L).Given that CL@ is 7.5 L/d,
Figure lB indicates that CL@ (and hence total clearance)
changes only marginally over this dosing range.
Although this report focuses on the relations among intake,
plasma concentrations, and renal excretion of ascorbic acid, the
manner in which tissue concentrations of the vitamin relate to
Daily dosing rate (mgld)
B
s@o
Daily dosing rate (mgld)
FIGURE5.Modelpredictionsoftheinfluenceofrenalfunctiononthe
steady state plasma concentration of ascorbic acid. With a decrease in renal
functionfrom 100%to 10%ofnormal (ie, 173lid), the steady state plasma
concentration is expected to increase, but only marginally, up to daily
doses of 1000 mg (5.7 mmol) (A). At still higher doses, however, plasma
concentration increases sharply in subjects with poor (10%) renal function
(B).Themodelassumesthatthe glomerularfiltrationrateand the maxi
mum rate for tubular reabsorptiondecline in proportion with renal function,
and takes into account the capacity-limitedabsorption with increasing dose
(Figure 3). The bioavailability represented in the figure was approximated
by using an empirical relation to describe the tendency for bioavailability
to decreasewithan increasein the dailydosingrate.
these indexes is also important. Because of the ethical and legal
issues associated with obtaining tissue concentrations in hu
mans, most data pertaining to tissue concentrations of ascorbic
acid have been obtained in animals. However, the validity of
extrapolating animal data to humans is questionable because
most animals can synthesizetheir ascorbic acid requirement
endogenously. In those few animals in which ascorbic acid
must be supplied exogenously (eg, guinea pigs), the metabo
lism of the vitamin differs from that in humans (13). Evidence
in the literature from human studies indicates that ascorbic acid
circulates in the plasma exclusively in its reduced form and
unbound to protein (30). Furthermore, it is freely transported
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1170
BLANCHARD ET AL
into cells, including leukocytes and red blood cells. The data
indicate that as the ascorbic acid intake increases, the plasma
concentration increases in an approximately hyperbolic man
ncr, reaching a plateau at 12—15mgfL (68.1—85.2p@mol/L)at a
dose of 90—150mg (0.5—0.9mmol)/d. The relation between the
daily dose and the ascorbic acid concentration in leukocytes is
similar except that tissue concentrations are usually 3—10times
higher than plasma concentrations. Thus, up to an intake of
c#49Ømg (0.5 mmol)/d, concentrations of ascorbic acid in
plasma and tissues are directly related, although not linearly,
both to each other and to the ascorbic acid intake (31). Because
of the nonlinearity of intestinal absorption and renal excretion
of ascorbic acid, both plasma concentrations and the total body
pool size tend to reach plateaus.
Renal function is of little concern when one takes doses at or
near the RDA for ascorbic acid because renal excretion con
tributes negligibly to overall elimination at this dose. This
likely explains why we found no reported studies on the han
dung of ascorbic acid in subjects with severely compromised
renal function. However, the issue of renal function becomes
more important when megadoses of ascorbic acid are taken
because renal excretion then becomes a more significant elim
ination pathway. The model proposed here is useful in sorting
out the relative contributions of saturable gastrointestinal ab
sorption and renal tubular reabsorption to the observed ceiling
in plasma concentrations.
In applying the model it was assumed that the glomerular
filtration rate and the maximal rate of tubular reabsorption for
renal tubular reabsorption decline in proportion with renal
function. This model is consistent with the limited available
supportive data provided by Oreopoulus et al (32), who found
that the ratio of the maximal rate of tubular reabsorption to the
glomerular filtration rate was constantwith agefor males and
females. How the steady state plasma ascorbic acid concentra
tion changes as the daily oral dosing rate of ascorbic acid
increases, as renal function declines from 100% to 10% of
normal, is shown in Figure 5. These simulations indicate that
plasma concentrations are not affected greatly by diminished
renal function at doses up to 1 g (5.7 mmol). However, in
subjects with severely impaired renal function ( 10% of nor
mal), the model predicts plasma concentrations in excess of 40
mg/L (227. 1 @.amol/L)at doses of@ 10 g (56.8 mmol) (Figure
SB). These predictions suggest the need for studies in this
potentially vulnerable group.
In contrast with CLR, the amount absorbed (calculated from
the percentage absorbed multiplied by the administered dose)
increased only from 160 to 325 mg (0.9 to 1.8 mmol) over the
daily dose range of 200-2500 mg (1.1—14.2mmol), as shown in
Table 1. These observations imply that saturability of the
absorption process is primarily responsible for the relative
constancy of the steady state plasma concentrations within this
dose range. Regardless of the cause of this ceiling effect, the
result is that there is clearly no pharmacokinetic justification
for taking ascorbic acid orally in megadose quantities unless
megadoses exert a favorable effect in the gastrointestinal
tract that outweighs their adverse effects. A
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1171
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APPENDIX A
The model used by Ralli et al (1) to describe the renal
excretion of ascorbic acid is discussed below. This model is
based on the knowledge that ascorbic acid is not bound to
plasma proteins (2) and is filtered and actively reabsorbed
in the renal tubules by a saturable process, as shown in
Figure Al.
The rate of renal excretion can therefore be expressed as the
rate of filtration minus the rate of tubular reabsorption, ie,
(reabsorption) (Al)
where CL@is renal clearance, C@is the steady state plasma
concentration, GFR is the glomerular filtration rate, and Tr is
the rate of renal tubular reabsorption. Assuming that the prox
imal tubular lumen fluids are well mixed, the effective ascorbic
acid concentration for carrier-mediated transport (C@ff)is the
same as that leaving the transport site within the tubule. The
rate of excretion is thus equal to GFR X C@ffif little or no water
reabsorption has occurred. Consequently,
G@XC@ff=GFRXC.4u@Tr (A2)
The reabsorption process is saturable and can be expressed by
the following transport model: REFERENCES
Tm X Ceff
Tr= K+CCff
where Tm is the maximum rate of tubular reabsorption and K
is the transport constant.
Glomerulus Proximal Tubule
FIGURE Al. Schematic model for renal handling of ascorbic acid. The vitamin is filtered at a rate equal to the glomerular filtration rate (GFR) times
plasma concentration (C) because there is no binding to plasma proteins. Facilitated reabsorption occurs in the proximal tubule. The region of transport
is considered to be a well-stirred compartment. The effective concentration (Ceff) for the transport is the same as that leaving the transport site, on the
assumption that no water has been reabsorbed. Therefore, the rate of excretion is GFR X C@ff.
Substitution of the value of Ceff from equation A3 into A2
results in the equation used by Ralli et al (1):
I Tr \/Tm—Tr\
K=@_@)@ Tr ) (A4)
Rearrangement of equation A4 produces the following:
ITrXK\ /Tr\
C's = @Tm—¿ Tr)@ @) (AS)
For the simulations used here, a Tm of 2800 mg/d, a K of 1.7
@mol/L,and a GFR of 120 mLlmin (173 lid) were derived
empirically to obtain a visual fit of the data. A statistical fit to
obtain the model parameters did not seem appropriate because
the data were derived from studies in which the sources of error
were different. These values are similar to those used by Ralli
et al (1).
From equation Al we also obtain
Tr
CLR GFR - @;; (A6)
At steady state, the daily rate of absorption (R), given as the
oral bioavailability (F) times the daily dosing rate (mg/d), is
equal to the daily rate of elimination (CL,@.X C5), ie,
R = F X dailydosing rate= CL@x C's' (A7)
where CLI. (total clearance) = CLR (renal clearance)
+ CL@ (nonrenal clearance) (A8)
The value of CL@ was estimated as the reciprocal of the
slope of a plot (Figure 5 of reference 7) of C@ versus R at low
R values when all ingested ascorbic acid is absorbed (F = 1)
and CLR is negligible and, therefore, CLI. CL@, ie, from
equation A7:
/l\ I 1 \
Cs = @L:;) X R @j;;) X R (A9)
1. Ralli EP, Friedman GJ, Rubin SH. The mechanism of the excretion of
(A3) vitaminC by thehumankidney.J ClinInvest l940;l7:765—70.
2. Levine M, Dhariwal KR, Washko PW, et al. Ascorbic acid and in situ
kinetics: a new approach to vitamin requirements. Am J Clin Nutr
1991;54(suppl): 1157S—62S.
CLR X C@
(excretion)
= GFRXC'4@ -
(filtration)
Tr
Filtration Reabsorption Excretion
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... However, we did see that the low-volume group had significantly fewer overall adverse events and less vomiting and nausea than did the standard-volume group. This significant difference may result from the safety of ascorbic acid, even at high doses [54], [55], and the lower volume of PEG, reducing any PEG-based electrolyte or volume alterations [34]. ...
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