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Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425
3To whom correspondence should be addressed. E-mail: wallet{at}musc.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • quercetin • intestinal absorption • enterohepatic recirculation • carbon dioxide formation • flavonoids • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–3)
. Epidemiologic studies suggest that
flavonoids are protective against coronary heart disease and stroke
(4
–6)
as well as in certain cancers (7
–9)
.
Large numbers of in vitro studies suggest a variety of molecular
targets for these effects (10)
. The numerous reports on
quercetin’s potential beneficial effects on human health have more
recently led to a proliferation of high dose quercetin nutraceutical
preparations. However, a major concern has been the poor oral
bioavailability of quercetin and most other flavonoids
(11)
.
The original model of flavonoid absorption assumed that flavonoid
glucosides were too polar to be absorbed from the small intestine and
that absorption was dependent on the cleavage of the ß-glucoside
linkage by the colonic microflora (12)
. In 1995, Hollman
et al. (13)
indirectly calculated the absorption of
quercetin glucosides from an onion meal in ileostomy patients. The
authors proposed that these glucosides were actively absorbed via the
intestinal glucose transporter. However, there were no direct
measurements of the quercetin glucosides in the ileostomy fluid or
plasma to support such a conclusion. In contrast, in vitro studies
using human intestinal Caco-2 cell monolayers as a model of human
intestinal absorption showed complete lack of absorption of the
glucosides, mainly due to effective efflux by the multidrug resistance
protein 2 transporter (MRP2) (14
,15)
, whereas
quercetin itself was easily absorbed (16)
. In a subsequent
reinvestigation of the absorption of the quercetin glucosides in
ileostomy patients, we found that the glucosides were efficiently
hydrolyzed in the small intestine, potentially independently of
bacterial enzymes (17)
. This conclusion is supported by in
vitro studies (16
,18
–20)
. After hydrolysis of the
glucosides in the ileostomy patients, it was calculated that the
absorption of the quercetin aglycone may be as high as 65–81%
(17)
.
On the basis of these observations, we focused our attention on the
absorption and the biological fate of the quercetin aglycone.
14C-Labeled quercetin (Fig. 1
) was administered both orally and intravenously
(iv)4
to normal, healthy volunteers, greatly facilitating estimates of
recoveries and fraction absorbed. A large fraction of the oral dose of
quercetin was absorbed. Surprisingly, the main route of elimination of
quercetin, by both routes of administration, was via exhalation of
carbon dioxide.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Six healthy subjects (23–44 y; 70–110 kg) participated in the study.
Two subjects were female; one was Asian and five were Caucasian.
Written informed consents were obtained. The study was approved by the
Institutional Review Board for Human Research. The oral and iv
radiation doses were estimated to be 
1% of the annual
whole-body background radiation in the United States. All subjects
were studied in a Clinical Research Unit. The diet during and for
4 d before the study was low in flavonoids. Oral (6 subjects) and
iv (4 subjects) quercetin doses, at least 10 d apart, were
administered in the morning after an overnight fast. Breakfast was
served 3 h later. Serial blood samples drawn at 0–72 h after the
dose were centrifuged at 1000 x g for 10 min to
separate plasma; six 12-h urine samples were collected with thimerosal
and sodium bisulfite as preservatives. Stools were collected for
72 h and homogenized with 1 mol/L acetic acid. Aliquots of all
samples were stored at -20°C. In some subjects, samples of exhaled
air were also collected (see below).
14C-Quercetin doses.
The oral 14C-quercetin dose consisted of 112 mg quercetin dihydrate (100 mg, 330 µmol quercetin) and 10 mg ascorbic acid (Sigma, St. Louis, MO), dissolved in 9 mL ethanol, with 1.85 MBq (50 µCi) 14C-quercetin [1960 MBq/mmol; NCI Radiochemical Repository at Chemsyn Science Laboratories, Lenexa, KS] added in 50 µL dimethyl sulfoxide. Immediately before administration, 30 mL of Simple Syrup (Humco, Texarkana, TX) and 1 mL vanilla extract were added with vigorous shaking to form a suspension. The oral dose was followed by 500 mL of water.
For the iv 14C-quercetin doses, 2.5 mg 14C-quercetin [14.8 MBq] was dissolved in 4 mL 100% ethanol and sterilized by filtration. The solution was tested for sterility and pyrogens and stored at -80°C. Immediately before administration, 0.6 mL of this solution was added to 11.4 mL sterile saline and 10 mL [0.3 mg, 1 µmol 14C-quercetin, 1.85 MBq (50 µCi)] was infused with an equal volume of saline over 10 min. The infusion line was then rapidly flushed with 10 mL saline.
Sample analysis.
Plasma and urine samples (in duplicates) were counted directly after
the addition of an equal volume of water and 10 mL Aquasol-2
scintillation cocktail (Packard, Meriden, CT). The radioactivity
content in the fecal homogenates was estimated by freeze-drying
duplicate 2-g aliquots and extracting them with 3 x 10 mL
methanol. Aliquots of the methanol extracts were counted. The counts in
the third extract were <1% of those in the first. Exhaled
14CO2 was measured by an adaptation of the
erythromycin breath test (21)
. Hyamine hydroxide (1 mol/L
in methanol, J. T. Baker, Phillipsburg, NJ) was mixed with an
equal volume of 100% ethanol and 50 mL/L of 1% thymolphthalein.
Aliquots (4.0 mL) of this blue solution were put into 20-mL glass
scintillation vials and capped tightly. At timed intervals before and
after the two 14C-quercetin doses, the subjects were
instructed to blow bubbles through a pipet with a one-way valve
into a collection vial until the solution turned colorless, at which
point 2 mmol of CO2 was trapped (1 min). The vials were
then tightly capped; after addition of Aquasol-2 and
dark-adaptation, they were counted for radioactivity. The predose
counts were 10 dpm/sample, whereas the peak counts after both oral
and iv doses were 10,000–40,000 dpm/sample.
Calculations.
The areas under the plasma concentration vs. time curves (AUC) were
calculated by the trapezoidal rule to the last time point, 72 h.
The plasma, urine and exhaled carbon dioxide half-lives were
calculated by least-squares linear regression. The fraction of the
oral dose absorbed (in %) was calculated as
(AUCoral · Doseiv)/(AUCiv · Doseoral) · 100.
For calculations of total amount of 14CO2
exhaled, the endogenous rate of production (ERP) of CO2 was
calculated as 5 mmol CO2/m2 body surface
area · min (21)
. The dpm exhaled during a collection
interval was calculated as dpm measured (corrected for
background) · ERP/2 (mmol). This value could then be expressed as a
percentage of the administered dose (110 x 106 dpm)
exhaled per hour. The AUC of the percentage of dose exhaled per hour
vs. time was finally calculated by the trapezoidal rule to give the
total fraction of the dose excreted as 14CO2.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). At 8 h after the dose, there was a second peak of 350 ng/mL
(1160 nmol/L). The plasma concentrations then declined exponentially
over the entire study period of 72 h. After an iv dose of 0.3 mg
14C-quercetin (1 µmol) in four
subjects, there was a rapid fall of the plasma concentrations of total
radioactivity over the first 4 h after the bolus injection,
indicating the distribution phase (22)
. The plasma
concentrations then fell in parallel with those after the oral dose for
the remainder of the study period.
|
). There was no statistical difference between the two routes of
administration in the limited number of individuals studied. The
interindividual variability in AUC values for the oral doses was less
than twofold, with even less variability for the iv doses (Table 1)
.
For the four individuals who received the iv doses, the absorption,
ranging from 36.4 to 53% of the dose, could for the first time be
directly determined for quercetin. It should be noted that measured and
calculated kinetic parameters in the single obese female subject (110
kg) did not differ from those obtained with the five subjects of normal
weight (70–89 kg).
|
). After the iv dose, the recoveries in urine were as high as
18.4–26.8% of the dose with only 1.5–5.0% found in the feces. Thus,
the overall recoveries in urine and feces were 3.5–8.3% after the
oral and 21.3–30.2% after the intravenous dose. Further studies
attempting to increase the recoveries of radioactivity, in particular
from feces, compared with the procedure described in Methods, gave no
improvement.
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. The curves for the two routes of administration were very similar
except for higher peak levels after the oral dose. The large
variability in the early part of the time courses is due mainly to the
fact that in some individuals,
14CO2 started to appear in
the expired air 4 h after the 14C-quercetin
dose, whereas in others not until 8 h after the dose. The
14CO2 formation/exhalation
accounted for 23.0–81.1% of the administered
14C-labeled quercetin doses, both oral and
intravenous (Table 2)
.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,13
,23
,24)
and that some biological activity may be
associated with such conjugates (23)
. Of greater
significance may be observations consistent with efficient hydrolysis
of the glucoside conjugates in the intestinal lumen to the quercetin
aglycone (17
,20)
, which then appears to be efficiently
absorbed. The biological fate of the aglycone was the focus of the
present study.
In four subjects, who received both an oral and an iv dose of
14C-quercetin, we could for the first time
establish the oral absorption of this flavonoid, taking into account a
variety of metabolic and chemical breakdown products. The absorption
was surprisingly high, ranging from 36 to 53%. This had previously
been suggested on the basis of studies in a preclinical absorption
model, the Caco-2 cell monolayer (16)
. After
administration of the quercetin glucosides in ileostomy patients, the
absorption of quercetin after enzymatic hydrolysis of the
glucosides was calculated to be as high as 65–85% (17)
.
The dietary quercetin glucosides may thus, as suggested, act as more
soluble quercetin prodrugs with favorable absorption (17)
.
The terminal elimination half-life for the total quercetin
radioactivity was quite long, i.e., 20–72 h. This should be compared
with that of quercetin alone, which was only 0.7–2.4 h after iv
administration in two previous studies (22
,25)
. When
quercetin or quercetin glycosides were administered orally
(24
,26)
, half-lives for quercetin of 15–28 h have
been reported. However, this was after acid or enzymatic hydrolysis of
the samples and would thus be expected to reflect quercetin conjugates.
The very long half-life observed in our study could be due to
multiple factors. A high volume of distribution does not seem to be a
significant contributor. The volume of distribution for quercetin
itself is thus <0.5 L/kg (22
,25)
and for the total
radioactivity in this study, 1.4 L/kg. A more likely explanation is
enterohepatic recirculation, which may replenish the plasma
concentrations over an extended time period. There was very strong
evidence for such recirculation after the oral dose, with all subjects
showing a distinct second peak of plasma radioactivity 6–12 h after
the dose, although there was only weak evidence after the iv dose (Fig. 2)
. An additional factor, which is the subject of a separate
investigation (27)
, is the potential for covalent binding
of quercetin to plasma proteins, presumably after initial enzymatic
bioactivation.
The most challenging part of the disposition of quercetin in humans was
the metabolic fate, including the route(s) of elimination, which
required the use of radioactively labeled compound. The recoveries in
both urine and feces after the oral dose were very low, amounting to
<10% of the dose. The much higher recovery (20%) in the urine
after the iv dose was interesting. This may be an effect of the much
lower dose given iv (0.3 mg) compared with the oral dose (100 mg). Such
an effect may be explained by saturation of an efflux transporter in
the kidney after the higher oral dose. However, the major fraction of
both doses was still unaccounted for, suggesting an alternative route
of elimination.
This was explored by measuring potential exhalation of radioactivity in
the form of 14CO2, after
both oral and iv doses. It was fortuitous that we were able to detect
this major metabolic route because the
14C-quercetin used has only one of its 14 carbon
atoms labeled, i.e., the one in the 4-position (Fig. 1)
. The total
recoveries of 14C-quercetin in urine, feces and
exhaled air in the individuals in Table 2
amounted to 46.7–106.2% of
the dose. The reason for this variability in the recoveries of the
14CO2 excretory route is
not known. There has been one previous study with
14C-quercetin administration, in this case in
rats, in a study previously receiving little attention
(28)
. In that study,
14CO2 exhalation occurred
as well. Also, when 14C-quercetin was incubated
with rat gut contents, large amounts of
14CO2 were produced. Thus,
we conclude that the 14CO2
exhalation in the subjects receiving
14C-quercetin most likely originated from the
intestine. This is supported by the finding that in all subjects,
negligible amounts of CO2 were formed before
4 h. The efficiency of this total metabolic breakdown of quercetin
is likely enhanced by enterohepatic recirculation. The detailed pathway
followed for the abundant CO2 formation from
quercetin is not understood. It may be a combination of bacterial
enzyme–mediated and strictly chemical (nonenzymatic) reactions
(29
,30)
. This warrants further studies.
Although the use of 14C-quercetin with the
labeled carbon atom in the 4-position of the C-ring (see Fig. 1
) as
the dosage form provided a number of critically important pieces of
information regarding the biological fate of this flavonoid in humans,
it also left some unanswered questions. The substantial loss of
14CO2, ranging from 23 to
81%, means that a large proportion of the dose not retaining the
14C-label was unaccounted for. This would be
expected to include small phenolic carboxylic acids derived either from
the A-ring or the B-ring (11
,29
,30)
, which would
be expected to be excreted mainly in urine (30)
. Because
the C-ring of quercetin is opened and cleaved in this process,
complete recovery of the radioactive doses of quercetin would require
specific labeling of both the A- and the B-ring.
Of key importance now is to attempt to define the nature of the
radioactivity in plasma. Preliminary measurements support previous
observations (17
,23
,24
,31)
that there is no unchanged
quercetin in plasma after oral doses. The main metabolites may be
glucuronic acid conjugates (17)
, recently confirmed by
mass spectrometry (31)
. Such conjugates may have
antioxidant activity (32)
. However, other metabolites with
potential antioxidant activity (23)
, including glutathione
conjugates (33)
and small phenolic carboxylic acids (see
above), cannot be excluded. Alternatively, it may consist of labile
covalent adducts to plasma proteins, as recently suggested
(27)
. These studies are currently in progress.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by the National Institutes of Health grants GM55561 and RR01070.
4 Abbreviations used: AUC, area under the curve; ERP, endogenous rate of production; iv, intravenous;
Manuscript received May 8, 2001. Initial review completed June 21, 2001. Revision accepted July 12, 2001.
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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