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Journal of the American College of Nutrition
ISSN: 0731-5724 (Print) 1541-1087 (Online) Journal homepage: http://www.tandfonline.com/loi/uacn20
A Comparative Pharmacokinetic Assessment of a
Novel Highly Bioavailable Curcumin Formulation
with 95% Curcumin: A Randomized, Double-Blind,
Crossover Study
Sidney J. Stohs, Jin Ji, Luke R. Bucci & Harry G. Preuss
To cite this article: Sidney J. Stohs, Jin Ji, Luke R. Bucci & Harry G. Preuss (2017): A
Comparative Pharmacokinetic Assessment of a Novel Highly Bioavailable Curcumin Formulation
with 95% Curcumin: A Randomized, Double-Blind, Crossover Study, Journal of the American
College of Nutrition, DOI: 10.1080/07315724.2017.1358118
To link to this article: http://dx.doi.org/10.1080/07315724.2017.1358118
© 2017 The Author(s)© Sidney J. Stohs, Jin Ji,
Luke R. Bucci, and Harry G. Preuss
Published online: 18 Oct 2017.
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A Comparative Pharmacokinetic Assessment of a Novel Highly Bioavailable Curcumin
Formulation with 95% Curcumin: A Randomized, Double-Blind, Crossover Study
Sidney J. Stohs, PhD, FACN, CNS
a
, Jin Ji, Ph.D.
b
, Luke R. Bucci, PhD, CNS
c
, and Harry G. Preuss, MD, MACN, CNS
d
a
School of Pharmacy and Health Professions, Creighton University Medical Center, Omaha, Nebraska, USA;
b
Brunswick Laboratories,
Southborough, Massachusetts, USA;
c
Interpath Nutrition, Reno, Nevada, USA;
d
Department of Biochemistry, Georgetown University
Medical Center, Washington, DC, USA
ARTICLE HISTORY
Received 5 May 2017
Accepted 18 July 2017
ABSTRACT
Objective: Curcumin exhibits many beneficial health-promoting characteristics. However, its poor oral
absorption precludes its general use. This study assessed the bioavailability of a novel curcumin
formulation compared to 95% curcumin and published results for various other curcumin formulations.
Methods: A randomized, crossover, double-blind, comparator-controlled pharmacokinetic study was
performed in 12 healthy adult subjects to determine the appearance of free curcumin and its metabolites
curcumin sulfate and curcumin glucuronide in plasma after a single dose of a novel proprietary curcumin
liquid droplet micromicellar formulation (CLDM) and unformulated 95% curcumin powder in capsule form.
An equivalent 400-mg dose of each product was administered. The 95% curcumin contained 323 mg
curcumin, and the CLDM contained 64.6 mg curcumin. Blood samples were drawn and plasma was
analyzed for curcumin and its 2 conjugates without enzymatic hydrolysis by liquid chromatography–
tandem mass spectroscopy.
Results: Plasma levels of curcumin sulfate and curcumin glucuronide after 1.5 hours from CLDM were
approximately 20 and 300 ng/mL, respectively, whereas the levels for 95% curcumin were near baseline.
Free curcumin reached a maximum level of 2 ng/mL for CLDM and 0.3 ng/mL for 95% curcumin at
1.5 hours. For the CLDM, a small secondary free curcumin peak occurred at 12 hours and a tertiary 1.5-ng/
mL peak occurred at 24 hours. The total curcumin absorbed as represented by the area under the curve
(AUC)/mg administered curcumin for CLDM was 522 times greater than for the 95% curcumin.
Conclusions: The novel CLDM formulation facilitates absorption and produces exceedingly high plasma
levels of both conjugated and total curcumin compared to 95% curcumin. A comparison of the C
max
/mg
curcumin and AUC/mg of administered curcumin for CLDM with data from pharmacokinetic studies of
various enhanced absorption formulations indicate that the greatest absorption and bioavailability are
produced with the novel CLDM formulation.
KEYWORDS
Curcumin; curcumin sulfate;
curcumin glucuronide;
bioavailability;
pharmacokinetics
Introduction
Turmeric is a spice and coloring agent derived from the rhi-
zomes of Curcuma longa L., which has also been used for centu-
ries in traditional medicines (1,2). Curcumin is the primary
polyphenol present in turmeric with small amounts of
demethoxycurcumin and bisdemethoxycurcumin (1). These cur-
cuminoids are the major bioactive components responsible for
the nutritional and pharmacological activities of turmeric (2–10).
Numerous human clinical, animal, and in vitro studies have
examined and demonstrated the health benefits of curcumin,
including disease-preventive, antioxidant, anti-inflammatory,
tissue protective, immunoprotective, antibacterial, antifungal,
antiviral, antineoplastic, metabolism modulating, and antidepres-
sant properties (3–10).
The molecular mechanisms associated with the broad spec-
trum of actions are complex. Curcumin exerts a pleiotropic effect,
modulating and regulating multiple targets (2,5–7,10). Curcumin
inhibits pro-inflammatory transcription factors, including
nuclear factor-kappa B, activator of transcription-3, and wnt/
beta-caterin. Curcumin activates peroxisome proliferator–acti-
vated receptor gamma and Nrf2 cell signaling pathways, leading
to the downregulation of tumor necrosis factor, interleukin-6,
resistin, leptin, and monocyte chemostatic protein-1, and upregu-
lates adiponectin. Furthermore, curcumin modulates expression
of a host of enzymes and other gene products (5,7–10).These
diverse mechanisms account for the wide range of nutritional,
physiological, and pharmacological effects.
Despite the promising nutritional and pharmacological
properties of curcumin, curcumin exhibits low aqueous solubil-
ity, poor gastrointestinal absorption, and poor biodistribution
(4–8,11–14). Furthermore, curcumin has a high rate of metabo-
lism and metabolic inactivation and rapid elimination from the
CONTACT Sidney J. Stohs, PhD, FACN, CNS sid.stohs9@gmail.com School of Pharmacy and Health Professions, Creighton University Medical Center, 2500
California Plaza, Omaha, NE 75034.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/uacn.
© 2017 Sidney J. Stohs, Jin Ji, Luke R. Bucci, and Harry G. Preuss
This is an Open Access article. Non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly attributed, cited, and is not altered, transformed, or
built upon in any way, is permitted. The moral rights of the named author(s) have been asserted.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
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body (4,5,7,11–13). Curcumin undergoes rapid conjugation
with some metabolic reduction (13) and, as a consequence, cur-
cumin occurs in the blood primarily as the physiologically and
pharmacologically inactive curcumin sulfate and curcumin glu-
curonide with very little free curcumin (5,11–13). Small
amounts of curcumin are also reduced to dihydrocurcumin,
tetrahydrocurcumin, and hexahydrocurcumin, all of which
may have some physiological activity but are primarily conju-
gated as the inactive glucuronide (5,11,12). It has been sug-
gested that in addition to free curcumin, various degradation
and condensation products may have health benefits (14).
It is not clear in what form curcumin exists within tissues
and what constitutes the truly active form at the cellular and
molecular levels. The relative importance of the blood levels of
curcumin as well as its glucuronide and sulfate conjugates with
respect to physiological effects is also not well defined. Because
curcumin is known to be more physiologically active than its
conjugated forms, it is assumed that blood levels of free curcu-
min reflect greater physiological activity (5,11–14) and in order
to exert a physiological response, it must be absorbed. The low
bioavailability of curcumin limits its usefulness in general
health care and as an aid in managing various diseases.
Various approaches have been used (12,15–19) to overcome
the poor absorption, rapid metabolism, and poor bioavailability
of curcumin. These strategies have been reviewed and include
formulations with liposomes, micelles, or interaction with mac-
romolecules such as gelatin and polysaccharides such as
g-cyclodextrin (21) and galactomammans (12,32). Further-
more, various nanoparticulate preparations that have been
developed include nanoemulsions, nanomicelles, dendrimers,
conjugates, polymers, nanogels, and solid dispersions (16–19).
Although many formulations are effective in increasing absorb-
ability of curcumin, a number of the formulations have limita-
tions because the ingredients are not approved for food use,
due to the large delivery loads required, or because of regula-
tory issues (12).
All of these formulations have shown an increase in blood
levels of total curcumin. However, studies involving these diverse
formulations have not clearly shown an increase in free curcu-
min in the blood. With relatively few exceptions (30,33–37),
plasma samples are routinely subjected to enzymatic hydrolysis
due to the fact that the sulfate and glucuronide conjugates are
the predominant forms of curcumin. As a consequence, these
studies result in the subsequent measurement of total curcumin
and not free curcumin (21–29,31,32,38) and do not provide a
clear understanding of the potential pharmacokinetic benefits of
the formulations with respect to free curcumin.
A novel proprietary curcumin formulation involving liquid
droplet micromicellar (CLDM) technology has been developed
with food-grade materials, and preliminary studies indicate
that it has an exceedingly high (»300 ng/mL) bioavailability.
The present investigation is a randomized, double-blind, cross-
over study comparing the bioavailability of this novel curcumin
formulation with 95% curcumin in healthy subjects. This study
is unique in that this novel formulation results in exceedingly
high plasma levels of free curcumin as well as its conjugates.
Because various formulations contain different amounts of
curcumin, we have calculated and compared the relative phar-
macokinetic efficiency on the basis of per milligram of
administered curcumin of this novel curcumin formulation
with published reports involving other formulations as well as
unformulated 95% curcumin.
Materials and methods
Curcumin study products
The novel proprietary CLDM formulation (BioCurc) used in
this study was developed and supplied by Boston BioPharm
(Southlake, TX). The 95% curcumin (curcuminoids) used as
such and in the formulation was obtained from Novel Ingre-
dients (East Hanover, NJ; Lot #650036563) and was composed
of approximately 85% curcumin, 13% demethoxycurcumin,
and 2% bisdemethoxycurcumin. The primary constituents of
the study product included 64.6 mg curcumin (76 mg total cur-
cuminoids), lauryl macrogol-32 glycerides, polysorbate-20, DL-
alpha-tocopherol, and hydroxypropyl cellulose and was deliv-
ered in 6 capsules. The comparator product contained 323 mg
95% curcumin (380 mg total curcuminoids) and hydroxypropyl
cellulose in 6 capsules. The study was approved by Institutional
Review Board Services (Pro00011961). The study was con-
ducted by KGK Synergize Inc., ClinicalTrials.gov Identifier
NCT02474953.
Subjects
This was a double-blind, randomized, crossover study consist-
ing of healthy adult volunteers (6 male and 6 female) between
the ages of 18 and 45 years with a body mass index (BMI) of
18–29.9 kg/m
2
. Inclusion criteria were as follows: If female, was
not of childbearing potential or was using a medically approved
method of birth control and had a negative urine pregnancy
test result. The subjects agreed to maintain their current levels
of physical activity throughout the study and avoided using
black or white pepper, turmeric, curcumin, or curry; yellow dye
#E100 in the preparation of food; and Indian and Thai cuisines
for the 7-day period prior to the study and for the period of the
study. The subjects agreed to avoid alcohol and caffeine for
12 hours and grapefruit and grapefruit juice for 48 hours prior
to baseline and each subsequent clinic visit. Furthermore, the
subjects agreed to consume only low polyphenols in the diet
(nutritionists counseled on high-polyphenol fruits, vegetables,
supplements, herbal extracts, and whole-grain based foods to
avoid) 3 days prior to baseline and on test days. Finally, the
subjects gave written informed consent to participate in the
study.
Exclusion criteria included a BMI 30 kg/m
2
; women who
were pregnant, breastfeeding, or planning to become pregnant
during the course of the trial; subjects with unstable medical
conditions as determined by the qualified investigator; subjects
who were smokers; subjects who used St. Johns’wort 3 weeks
prior to baseline and during the study; subjects with current or
history of gastrointestinal problems or disease; subjects with
metabolic, endocrine, or chronic diseases; immunocompro-
mised individuals; subjects with clinically significant abnormal
lab results at screening; subjects who had planned surgery dur-
ing the course of the trial; subjects with a history of or current
diagnosis of any cancer or history of gallbladder issues; subjects
with hyperacidity; and subjects with gastric/duodenal ulcers. In
2 S. J. STOHS ET AL.
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addition, subjects were excluded if they had prior use of pre-
scription H2 blockers, proton pump inhibitors, or blood sugar–
lowering agents; used blood pressure medication; had donated
blood in the last 2 months; had a history of blood/bleeding
disorders or were taking prescription blood thinners or anti-
platelet therapy; had a history of alcohol abuse (>2 standard
alcoholic drinks per day) or drug abuse within the past
6 months; used medical marijuana; were currently being treated
for hyperlipidemia or had high hypercholesterolemia including
the use of statins and cholestyramine; had participated in a
clinical research trial within 30 days prior to randomization;
had an allergy or sensitivity to study supplement ingredients or
to any food or beverage provided during the study; and were
unable to give informed consent.
Sixteen participants were recruited for the study. Four
female subjects did not complete the study. Two subjects did
not return for the second arm of the study. One subject with-
drew for a health reason unrelated to the study products, and
one subject withdrew during clinic visit 2 due to difficulty in
having blood drawn. The demographics of the subjects who
completed the study are presented in Table 1 by gender.
Experimental protocol
The consort chart is provided in Figure 1. At screening and
clinic visit 1, 42 subjects were initially screened, given the
informed consent form, asked to carefully read the information,
and given the opportunity to seek more information if needed.
If agreeable, each subject signed the consent form and received
a duplicate. Once consent was obtained, inclusion and exclu-
sion criteria were reviewed, medical history and concomitant
therapies and current health status were reviewed, seated rest-
ing blood pressure and heart rate were measured, weight and
height were measured and BMI was calculated, and a physical
exam was conducted. Female participants were given urinary
pregnancy tests, and fasting (8 hours) blood samples were col-
lected for complete blood counts, electrolytes (Na, K, Cl), fast-
ing glucose, creatinine, aspartate aminotransferase (AST),
alanine aminotransferase (ALT), gamma glutamyl transpepti-
dase (GGT), and bilirubin. Sixteen subjects (6 males and 10
females) qualified for the study based on the inclusion/exclu-
sion criteria.
At clinic visit 2, subjects were randomized and administered
a single 6-capsule dose of either the CLDM test product (76 mg
curcumin) or the comparator product (380 mg 95% curcumin).
Subjects swallowed the dose in the clinic on an empty stomach
with water after the predose blood sample had been obtained.
The time of dose was recorded and the timing of blood draws
was based on the dose time. Blood samples were drawn at
15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours,
4 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, and
14 hours postdose for analysis of plasma curcumin levels. All
subjects were provided the same meals on the 2 test days, and
the amounts consumed were recorded. Participants remained
in the clinic for the 14-hour time period.
Subjects returned to the clinic (visit 3) for the 24-hour blood
sample collection and for the 48-hour blood sample collection
(visit 4). There was a minimum of 14 days’washout prior to
the second test period (clinic visit 5) at which time the cross-
over product was given and the above procedure was repeated,
including clinic visits 6 and 7 for the 24- and 48-hour blood
sample collections, respectively. Twelve subjects (6 males and 6
females) completed the study and there were no adverse effects
observed or reported by any of the participants. One subject
Table 1. Demographic data for participants who completed the study.
a
Parameter Males Females
Age 28.7 §7.7 years 29.8 §6.7 years
Height 204.2 §27.4 cm 162.0 §28.4 cm
Weight 80.4 §10.8.3 kg 63.8 §11.2 kg
BMI 24.8 §3.1 kg/m
2
23.6 §3.4 kg/m
2
BMI Dbody mass index.
a
Six males and 6 females. Results are presented as mean §SD.
Figure 1. Consort chart.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 3
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withdrew consent and elected not to participate prior to visit 2.
Two female subjects were lost after completion of arm 1, visit 4.
One was lost to follow-up and the other withdrew for personal
reasons. One subject was a no-show for the final visit (visit 7;
see Figure 1).
Analytical methods
Blood samples (minimum of 6 mL of whole blood each) were
collected in vacutainer tubes with EDTA as the anticoagulant.
The samples were immediately centrifuged at 2500 gat 4C for
15 minutes, and 3 aliquots of 1-mL plasma supernatant, with-
out disturbing the white buffy layer, were collected and depos-
ited into cryotubes, which were then frozen and stored at
¡80C until analysis. The samples were extracted according to
the method of Cao et al. (20).
The samples were analyzed for free curcumin, curcumin sul-
fate, and curcumin glucuronide by high-performance liquid
chromatography–tandem mass spectrometry using a Waters
Atlantis C-18 column (2.1 mm £50 mm, 3.0 mm) for the liq-
uid chromatography separation on a Shimadzu LC-20AT sys-
tem and a negative ion mode, multiple reaction monitoring
tandem mass spectrometry method for compound quantifica-
tion with an AB Sciex 4000 Q trap system and a triple quadru-
pole mass spectrometer (Shimadzu Corp., Kyoto, Japan). The
daughter ions of compounds were determined by fragmenta-
tion experiments and the most abundant daughter ions were
selected for compound quantifications (20). The developed
method was applied to quantify curcumin and its targeted
metabolites.
Curcumin standards
Calibration curves were prepared using human blood plasma
spiked with standard solutions extracted side by side with the
test plasma samples. Calibration curves were prepared for
curcumin, curcumin glucuronide, and curcumin sulfate. Curcu-
min was purchased from Sigma Aldrich (St. Louis, MO,
USA), curcumin sulfate was obtained from TLC Pharmaceu-
tical Standards (Aurora, ON, Canada), and curcumin glucu-
ronide was procured from Toronto Research Chemicals Inc.
(Toronto, ON, Canada). Correlation coefficients for all meth-
ods achieved R
2
values >0.990.
Statistical analysis
Statistical analyses were performed with GraphPad Prism 7.0 (La
Jolla, CA, USA). A paired 2-tailed ttest was used to compare
C
max
values between 95% curcumin and CLDM periods. Area
under the curve (AUC), k
elim
,andt
1/2
were determined by
GraphPad Prism. The built-in XY nonlinear regression curve
analysis for AUC in GraphPad Prism was employed which uses
the standard trapezoidal rule to calculate peak areas. Because
some subjects showed no apparent uptake of curucmin, post hoc
responder rates of C
max
for total curcumin were determined by
comparison to 2 published studies that used a similar dose of
95%curcuminasinthecurrentstudy(39,40).Basedonthe
results of these studies, an average C
max
of 20 ng/mL was used as
a threshold of response for chi-square analysis with Yates
correction.
Results
Numerous human pharmacokinetic studies have been con-
ducted with 95% curcumin (curcuminoids). This study com-
pared the pharmacokinetic properties of unformulated 95%
curcumin with the novel CLDM, BioCurc, under the same
experimental conditions and in the same subjects. Plasma
blood levels of curcumin glucuronide, curcumin sulfate, free
curcumin, and total curcumin are presented in Figure 2, after
orally ingesting capsules of either the CLDM, which delivered
Figure 2. Plasma levels of curcumin glucuronide, curcumin sulfate, free curcumin, and total curcumin after a single dose of the study products.
4 S. J. STOHS ET AL.
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76 mg curcumin, or the unformulated 95% curcumin, which
delivered 380 mg curcumin.
Although blood samples were drawn for a total of 48 hours,
the data are presented only for 8 hours for the glucuronide, sul-
fate, and total curcumin, which were close to baseline at this
time point. After administration of the novel CLDM, highest
plasma levels were achieved with curcumin glucuronide, which
reached almost 300 ng/mL at 1.5 hours postdosing (Figure 2A).
Under the same conditions, plasma curcumin glucuronide fol-
lowing administration of 5-fold more curcumin associated with
the unformulated 95% curcumin achieved peak levels that were
near baseline (approximately 1 ng/mL).
The novel CLDM study product resulted in plasma levels of
curcumin sulfate at the 1.5-hour time point that reached
approximately 20 ng/mL, as compared to plasma levels for this
metabolite associated with 95% curcumin that were approxi-
mately 1 ng/mL (Figure 2B). The data for free curcumin are
presented over 48 hours following administration of the 2
products (Figure 2C). Free curcumin reached a maximum
plasma level of approximately 2 ng/mL for the CLDM and
0.3 ng/mL for the 95% curcumin (Figure 2C) at the 1.5-hour
time point. However, a small secondary free curcumin peak
was observed for the CLDM at 12 hours, and a much larger
peak of approximately 1.5 ng/mL occurred at the 24-hour time
point. Free curcumin from administration of the 95% curcumin
remained near baseline over this period of time.
The total plasma curcumin over 8 hours is presented in
Figure 2D. Because total curcumin is usually measured and
reported after hydrolysis, and because the plasma samples
were not hydrolyzed in this study, total curcumin was
determined by correcting for actual curcumin content asso-
ciated with curcumin sulfate and curcumin glucuronide,
which was not done for the graphs of curcumin glucuronide
(Figure 2A) and curcumin sulfate (Figure 2B). As a conse-
quence, the amount of total curcumin (Figure 2D)appears
to be less than the amount of curcumin glucuronide
(Figure 2A). What is evident is the large peak of total cur-
cumin present in the plasma over the first 4 hours with a
C
max
of approximately 220 ng/mL for the novel CLDM
study product. The total curcumin in the plasma from the
unformulated 95% curcumin comparator remained near
baseline. The amount of total curcumin consisting of free
curcumin, curcumin glucuronide, and curcumin sulfate that
was absorbed as represented by the area under the curve
(AUC)/mg administered curcumin for the study product
was 94 times greater than for the 95% unformulated curcu-
min (Table 2).
Mean C
max
values (§standard error of the mean, SEM) for
total curcumin for CLDM and the unformulated 95% curcumin
were 277.24 §58.75 and 1.22 §0.31, respectively (p<0.0007,
paired 2-tailed ttest). The C
max
value for the study product was
116 times greater than for the 95% curcumin based on the
same amount of material (400 mg). However, when the data
were normalized for the relative amount of curcumin con-
sumed, the C
max
for the study product was over 1180 times
greater than for the unformulated 95% curcumin.
The T
max
,T
1/2
, and k
elim
values for free curcumin, curcumin
sulfate, curcumin glucuronide, and total curcumin for both
unformulated 95% curcumin and the CLDM study product are
presented in Table 2. In most other pharmacokinetic studies
involving curcumin formulations, these values are usually only
provided for total curcumin after enzymatic hydrolysis. The
T
max
for the total unformulated 95% curcumin and CLDM
were 8.6 §4.8 hours and 1.5 §0.07 hours.
Mean total curcumin AUC(0- to 8-hour) values (§SEM) for
the CLDM were 94 times greater than for the unformulated
95% curcumin (391.5 §86.42 vs 4.16 §1.25 ng-ml/h) at the
same 400-mg dose of material (Table 3). However, when the
data were normalized with respect to the amount of curcumin
ingested (64.6 mg for the CLDM vs 323 mg for 95% curcumin),
the AUC/mg of total curcumin for the study product was
522 times greater than for the 95% curcumin, denoting a vastly
greater absorption of total curcumin from the CLDM.
Responder rates were also calculated and compared.
Response was defined as a C
max
of 20 ng/ml or greater. No
unformulated 95% curcumin subjects attained this C
max
, but 11
out of 12 CLDM subjects attained this response. Corrected chi-
square analysis showed a significant difference for percentage
of responders for the CLDM (p<0.0001) compared to the
95% curcumin.
Discussion
The results of this study demonstrate that a novel proprietary
liquid droplet micromicellar formulation of curcumin facili-
tates absorption and produces exceedingly high plasma levels
of both conjugated and total curcumin compared to unformu-
lated 95% curcumin. Taken together, the C
max
and AUC data
based on the actual amount of curcumin ingested demonstrate
a marked superiority with respect to absorption and the plasma
levels achieved with the novel proprietary curcumin formula-
tion compared to the unformulated 95% curcumin. The CLDM
had been absorbed on hydroxypropyl cellulose to yield a flow-
able powder in order to facilitate capsule filling to match the
Table 2. T
max
and T
1/2
Values for unformulated 95% curcumin and BioCurc.
a
95% Curcumin BioCurc
Free Sulfate Glucuronide Total Free Sulfate Glucuronide Total
n7 9 1 9 10 12 11 12
T
max
(h) 4.0 4.0 4.0 8.6 3.8 1.6 1.6 1.5
T
max
SEM 1.67 1.32 0.00 4.84 2.38 0.08 0.11 0.07
k
elim
(ng/ml¢h) 0.126 0.363 0.300 0.310 0.429 3.912 141.9 33.66
T
1/2
(h) 5.5 1.9 2.3 2.2 1.6 0.18 0.005 0.021
SEM Dstandard error of the mean.
a
Each value is the mean of 12 subjects.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 5
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appearance of the unformulated 95% curcumin comparator
product. As noted above, due to the poor absorption of curcu-
min, various formulations have been developed to enhance the
bioavailability of curcumin (12–38).
In general, in order for a substance such as curcumin to
exert a systemic physiological response, it must be absorbed,
and pharmacokinetic studies are conducted to assess the extent
of absorption and the metabolic fate of the substance in ques-
tion. The novel CLDM formulation of curcumin assessed in
this study demonstrated greatly enhanced absorption compared
to unformulated 95% curcumin. The relative importance of the
blood levels of free curcumin and its glucuronide and sulfate
conjugates as opposed to total curcumin with respect to physio-
logical effects has yet to be determined.
Curcumin is physiologically more active than its conjugated
forms and therefore it is assumed that blood levels of free cur-
cumin reflect greater physiological activity (5,11–14). This
study has demonstrated measurable levels of free curcumin
associated with the novel proprietary curcumin formulation as
well as high levels of curcumin conjugates. Whether increased
and measurable blood levels of free curcumin are reflected in
enhanced tissue levels and greater physiological responses
remain to be determined, and subsequent studies are required
to address these questions.
The presence of an initial free curcumin peak at 1.5 hours
after administration of the CLDM study product followed by a
second peak at 12 hours and a third peak at 24 hours provides
new and interesting information (Figure 2C). How the novel
composition of the product influences the formation and
occurrence of these 3 peaks and subsequent physiological
responses remains to be determined. The second and third
peaks may reflect lymphatic uptake and enterohepatic recycling
with deconjugation, respectively (5,6).
It is exceedingly difficult to make direct pharmacokinetic
comparisons between various curcumin formulations that
contain widely differing amounts of curcumin, are delivered
in markedly differing amounts of total product mass, and
exhibit wide variations in the amount of curcumin absorbed
(12–32,38,39). For comparative purposes, published phar-
macokinetic data (C
max
and AUC) for 95% curcumin and
various enhanced absorption formulations are presented in
Table 3. The data have been normalized and are presented
as C
max
/mg curcumin and AUC/mg curcumin (Table 3),
permitting a more direct and simplified comparison with
respect to absorption and bioavailability and comparing the
amount of curcumin given to the subjects in these studies
with the amount occurring in the blood. Douglass and
Clouatre (12) developed a previous approach to this prob-
lem that involved equations for determining relative molar
absorption and relative mass efficiency that took into con-
sideration not only the relative amount of curcumin
administered but also the mass of the formulation.
Table 3 summarizes pharmacokinetic data from studies with
various formulations including micronized curcuminoids plus
turmeric oil (BCM-95); curcuminoids formulated with phos-
phatidylcholine from soy lecithin and microcrystalline cellulose
(Meriva); coadministered with piperine (Curcumin C
3
Com-
plex); complexed with fenugreek-derived galactomannan fiber
Table 3. Comparison of pharmacokinetic properties of various curcumin formulations.
Source Curcumin Dose (mg) Material Dose (mg) C
max
(ng/ml) C
max
/mg Curcumin AUC (ng¢h/ml) AUC/mg Curcumin Reference
95% Curcuminoids 323 400 1.22 0.0038 4.16 0.0104 Current
95% Curcuminoids 318 411 13.4 0.0421 49.9 0.1568 21
95% Curcuminoids 81 103 9.10 0.1129 14.3 0.1774 21
95% Curcumin 30 30 1.8 0.0600 4.1 0.1367 22
95% Curcuminoids 2920 4000 57 0.0195 929 0.3182 25
95% Curcumin 1900 2000 150 0.0789 462 0.2437 26
95% Curcuminoids 1295 1894 9.0 0.0069 122.5 0.0878 31
95% Curcuminoids 1350 1895 2.3 0.0017 10.8 0.0080 29
95% Curcuminoids 1774 1945 2.3 0.0013 19.7 0.0111 32
95% Curcuminoids 3240 3600 <1 NA NA NA 33, 34, 35
95% Curcuminoids CPiperine 9000 12,000 <1—ND ND 38
BioCurc 64.6 400 282 4.3653 351 5.4334 Current
Theracurmin 30 Drink 25.8 0.8600 121 4.0333 28
Theracurmin 30 250 29.5 0.9833 113 3.7667 22
Theracurmin 182 1500 231.5 1.2692 693 3.7993 27
Theracurmin 200 1667 222 1.1100 NA NA 24
Theracurmin 400 3330 511 1.2775 NA NA 24
CurQfen 97.7 250 341 3.4995 963 9.8567 21
CurQfen 391 1000 579 1.4808 2274 5.8159 21
Cavacurmin 371 2000 87.0 0.2342 389 1.0463 32
Longvida 163 650 22.4 0.1374 95.3 0.5828 30
CurcuWIN 376 1567 34.9 0.0928 380 1.011 29
BCM-95 279 500 45.0 0.1611 NA NA 27
BCM-95 376 NA 0.5 0.0013 5.8 0.0154 29
BCM-95 392 NA 1.1 0.0028 12.1 0.0309 32
BCM-95 1718 2000 573 0.3335 3588 2.0888 26
Meriva 152.5 58.5 0.3856 NA NA 27
Meriva 209 1110 69 0.3301 640 2.7948 31
Meriva 376 2000 207 0.6037 1336 3.5532 31
Meriva 376 8.7 0.0231 65.3 0.1737 29
Meriva 382 18.0 0.0471 86.9 0.2274 32
Meriva 303 2000 71 0.2343 785 2.591 25
NA Ddata not available, ND Dnot detected at 1 ng/mL.
6 S. J. STOHS ET AL.
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(CurQfen); complexed with a hydrophobic carrier, cellulosic
derivatives, and natural antioxidants (CurcuWIN); use of
microparticle and surface-controlled colloidal dispersion tech-
nology using ghatti gum and glycerin (Theracurmin); com-
plexed with g-cyclodextrin (Cavacurmin); and a solid lipid
curcumin particle (Longvida). The results of published phar-
macokinetic studies involving these formulations are compared
with the novel CLDM formulation used is the current study as
well as with the results from various studies using unformu-
lated 95% curcumin.
When one compares the C
max
/mg curcumin and AUC/mg
curcumin administered from the various pharmacokinetic
studies presented in Table 3, the data indicate that greatest
absorption and bioavailability are produced with the novel
CLDM formulation used in the current study. The products
that provide the closest absorption per milligram of curcumin
to the CLDM study product are the microparticle and surface-
controlled colloidal dispersion technology product using ghatti
gum and glycerin (Theracurmin) and the complex with fenu-
greek-derived galactomannan fiber (CurQfen). These products
are discussed in more detail below. The following are pharma-
cokinetic comparisons between the novel CLDM and various
other formulations based on published pharmacokinetic data.
The average C
max
/mg curcumin for the product based on
surface-controlled colloidal dispersion with ghatti gum and
glycerin (Theracurmin) from various studies is approximately
1.17 (22–24,29) compared to 4.37 for the new CLDM, suggest-
ing that the novel study product is approximately 3.7 times
more readily absorbable. Based on several studies for which
data are available, the AUC/mg curcumin administered is
approximately 5.43 for the CLDM compared to 3.9 for the
ghatti gum–glycerin-dispersed product (22,29), a factor of over
1.4 times.
If one uses the average C
max
/mg for the studies that exam-
ined the pharmacokinetic properties of the micronized curcu-
min with turmeric oil (BCM-95) (27,28), the C
max
/mg
curcumin for the novel study product is approximately 29 times
greater, and the AUC/mg curcumin is approximately 5.6 times
greater. A similar comparison with the phosphatidylcholine
formulated curcumin product (Meriva) indicated that the
C
max
/mg curcumin for the CLDM study product was approxi-
mately 8.6 times greater and the AUC/mg curcumin consumed
was approximately 2.2 t imes greater (Table 3).
Another absorption-enhanced product that is available is
composed of 20% curcumin, a hydrophilic carrier, cellulose
derivatives and antioxidants (CurcuWIN) (29). This product is
reported to have 46 times greater absorption than 95% curcu-
min (12,29). When comparing the C
max
/mg curcumin of this
product with that of the CLDM used in this study, the results
indicate that the CLDM produced a maximum concentration
that was approximately 47 times greater per milligrams of
ingested curcumin. When comparing the AUC/mg curcumin
administered, the value for the CNDL study product was
approximately 5.4 times greater (Table 3).
When the study product is compared to curcumin com-
plexed with g-cyclodextrin (Cavacurmin) (32), the C
max
/mg
and AUC/mg ingested curcumin for the novel study product
were approximately 18.7 and 5.2 times, respectively, greater for
the novel CLDM product (Table 3). Similarly, when comparing
the pharmacokinetic properties of a solid lipid curcumin parti-
cle (Longvida) with the CLDM study product, the C
max
/mg cur-
cumin and AUC/mg administered curcumin were
approximately 32 and 9.2 times greater for the study product,
respectively.
An inverted dose–response effect was observed with the cur-
cumin–galactomannan complex (CurQfen) (21). Another
pharmacokinetic study should be conducted with this product
to clarify the issue. When comparing the average of the 2 doses
of curcumin to the study product, the C
max
/mg curcumin and
AUC/mg curcumin values for the study product were approxi-
mately 1.9 times and equivalent, respectively. Several studies
have examined the pharmacokinetic properties of curcumin
coadministered with piperine (C
3
Complex) (33,34). The
results suggest that the C
max
/mg and the AUC/mg may be 22
and 1.9 times greater, respectively, for the novel CLDM study
product compared to this product.
When one examines the C
max
/mg curcumin and AUC/mg
curcumin values for unformulated 95% curcumin from various
studies (21,22,25–29,31,32,38–41), wide variations occur in the
values obtained (Table 3). Various reasons may exist for these
disparate results based on differences in the analytical protocols
including differences in doses given, manner of administration
(with or without food), extraction procedures, analytical and
quantitation methods, sample storage conditions, analytes
determined, and how end-points were calculated. Furthermore,
differences in sensitivity and specificity of the assay methods
may contribute to these widely varying results. With relatively
few exceptions (30,33–37), plasma samples in these studies
were enzymatically hydrolyzed resulting in the release of conju-
gated and bound curcumin. The average C
max
/mg curcumin
value for the 9 studies involving unformulated 95% curcumin
was approximately 0.03 ng/mL/mg total curcumin. In compari-
son, when free curcumin plus sulfate and glucuronide conju-
gated curcumin were analyzed without enzymatic hydrolysis as
was done in the current study, the C
max
observed for unformu-
lated 95% curcumin was only 0.003 ng/mL/mg curcumin.
The reason for this difference is not clear but may be due to
the effects of enzymatic hydrolysis and release of tissue-bound
curcumin. Similar results were observed regarding the AUC/
mg administered curcumin with respect to unformulated 95%
curcumin (Table 3). When one compares the average values for
C
max
/mg curcumin and AUC/mg ingested curcumin for unfor-
mulated 95% curcumin with the values for the CLDM study
product, the values for the study product are approximately
119 and 48 times greater, respectively. As a consequence, it can
be concluded that the novel study product exhibits much
greater absorbability per milligram of administered curcumin.
The results suggest that enzymatic hydrolysis of plasma
samples prior to analysis influences the analytical results and
does not provide any information regarding the amount of free
curcumin in the blood. Free, unconjugated curcumin and its
analogs compared to conjugated curcuminoids have been
shown to possess greater anti-inflammatory, antioxidant, tissue
protectant, and antiproliferative activities (5,42,43) and, as a
consequence, formulations that result in higher levels of free
curcumin may be expected to yield greater physiological effects.
A strength of the study was the use of the same subjects
under the identical experimental conditions to compare the
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 7
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absorption of the novel study product with 95% curcumin. In
addition, free curcumin, curcumin glucuronide, and curcumin
sulfate were analyzed without enzymatic hydrolysis, specifically
allowing quantitation of each of these 3 components. Most
other pharmacokinetic studies resort to enzymatic hydrolysis
to free curcumin from its conjugates and therefore the amounts
of each of the free and conjugated forms that are present in
plasma are not known (13–41). The total curcumin in the
plasma was calculated, allowing for the glucuronide and sulfate
components. The composition of the novel product involves
components that are all generally recognized as safe and there-
fore can be used in dietary supplements and food products.
A weakness of the study was the lack of determination of the
derivatives of curcumin, including demethoxycurcuin, bis-
demethoxycurcumin, dihydrocurcumin, tetrahydrocurcumin,
and hexahydrocurcumin. These metabolites of curcumin are
not determined in most studies. A need exists for a determina-
tion of the plasma levels of these constituents in order to better
understand the relationships between curcuminoid pharmaco-
kinetics and physiological/pharmacological effects. Further-
more, studies are required to assess the effects of the enhanced
absorption of curcumin associated with the CLDM product rel-
ative to specific physiological outcomes.
In summary, the novel CLDM product developed and
used in the current study exhibits very high gastrointestinal
absorption, which in general is greater than a variety of
enhanced absorption products for which pharmacokinetic
data are available. The AUC/mg administered curcumin
was approximately 417 times greater for the study product
than for unformulated 95% curcumin administered to the
same subjects and under the same experimental conditions.
This represents absorption greater than for any of the
known available products. Additional studies are needed to
confirm the results of this study and determine how the
enhanced absorption of this novel highly bioavailable form
of curcumin influences the effects of curcumin with respect
to specific health conditions as well as general health and
wellness.
Conflict of interest
S.J.S. and L.R.B. serve as consultants for Boston BioPharm Inc.
Funding
This study was funded by Healthy Directions, LLC (a Helen of Troy
Company), Bethesda, Maryland, and Boston BioPharm Inc., Boston,
Massachusetts.
References
1. Li S, Yuan W, Deng G, Wang P, Yang P, Aggarwal BB. Chemical com-
position and product quality control of turmeric (Curcuma longa L.).
Pharm Crop. 2011;2:28–54.
2. Amalraj A, Pius A, Gopi S, Gopi S. Biological activities of curcumi-
noids, other molecules from turmeric and their derivatives—a review.
J Tradit Complement Med. 2017;7:205–233.
3. Ak T, G€
ul¸cin I. Antioxidant and radical scavenging properties of cur-
cumin. Chem Biol Interact. 2008;174:27–37.
4. Jurenka JS. Anti-inflammatory properties of curcumin, a major con-
stituent of Curcuma longa: a review of preclinical and clinical
research. Altern Med Rev. 2009;14:141–153.
5. Prasad S, Tyagi AK, Aggarwal BB. Recent developments in
delivery, bioavailability, absorption and metabolism of curcumin:
the golden pigment from the golden spice. Cancer Res Treat.
2014;46:2–18.
6. Kocaadam B, Sanlier N. Curcumin, an active component of turmeric
(Curcuma longa), and its effects on health. Crit Rev Food Sci Nutr.
2015;13:2889–2895.
7. Kunnumakkara AB, Bordoloi D, Padmavathi G, Monisha J, Roy NK,
Prasad S, Aggarwal BB. Curcumin, the golden nutraceutical: multitar-
geting for multiple chronic diseases. Br J Pharmacol. 2016;174:1325–
1348.
8. Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-
Tortosa CM. Curcumin and health. Molecules. 2016;21:264;
doi:10.3390/molecules21020264.
9. Kotecha R, Takami A, Espinoza JL. Dietary phytochemicals and can-
cer chemoprevention: a review of the clinical evidence. Oncotarget.
2016;7:52517–52529.
10. Huminiecki L, Horbanczzuk J, Alanasov AG. The functional genome
studies of curcumin. Semin Cancer Biol. 2017; doi:10.1016/j.
semcancer.2017.04.002.
11. Pan MH, Huang TM, Lin JK. Biotransformation of curcumin through
reduction and glucuronidation in mice. Drug Metab Dispos.
1999;27:486–494.
12. Douglass BJ, Clouatre DL. Beyond yellow curry: Assessing commercial
curcumin absorption techniques. J Am Coll Nutr. 2015;34:347–358.
13. Vareed SK, Kakarala M, Ruffin MT, Crowell JA, Normolle DP, Djuric
Z, Brenner DE. Pharmacokinetics of curcumin conjugate metabolites
in healthy human subjects. Cancer Epidemiol Biomark Prev.
2008;17:1411–1417.
14. Janjun J, Wyganowska-Swiatkowska M, Detttlaff K, Jelinska A, Sur-
dacka A, Watrobska-Sweitlikowska D, Skrozypczak-Jankun E. Deter-
mining whether curcumin degradation/condensation is actually
bioactivation (review). Int J Mol Med. 2016;37:1151–1158.
15. Rahimi HR, Nedaeinia R, Shamloo AS, Nikdoust S, Oskuee RK. Novel
delivery system for natural products: nano-curcumin formulations.
Avicenna J Phytomed. 2016;6:383–398.
16. Mahran RI, Hagras MM, Sun D, Brenner DE. Bringing curcumin to
the clinic in cancer prevention: a review of strategies to enhance bio-
availability and efficacy. AAPS J. 2017;19:54–81.
17. Yallapu MM, Nagesh PK, Jaggi M, Chauhan SC. Therapeutic applica-
tions of curcumin nanoformulations. AAPS J. 2015;17:1341–1356.
18. Hussain Z, Thu HE, Ng SF, Khan S, Katas H. Nanoencapsulation, and
efficient and promising approach to maximize wound healing effi-
ciency of curcumin: a review of new trends and state-of-the-art. Col-
loids Surf B Biointerfaces. 2017;150:223–241.
19. Stanic Z. Curcumin, a compound from natural sources, a true scien-
tific challenge—a review. Plant Foods Hum Nutr. 2017;72:1–12.
20. Cao Y, Xu RX, Liu Z. A high-throughput quantification method
of curcuminoids and curcumin metabolites in human plasma via
high-performance liquid chromatography/tandem mass spectrom-
etry. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;949–
950:70–78.
21. Kumar D, Della J, Subash PS, Maliakkal A, Johannah NM, Ramadas-
san K, Balu M, Veera K, Krishnakumar IM. Enhanced bioavailability
and relative distribution of free (unconjugated) curcuminoids follow-
ing oral administration of a food-grade formulation with fenugreek
dietary fibre: a randomized double-blind crossover study. J Funct
Foods. 2016;22:478–587.
22. Sasaki H, Sunagawa Y, Takahashi K, Imaizumi A, Fukuda H, Hashi-
moto T, Wada H, Katanasaka Y, Kakeya H, Fujita M, et al. Innovative
preparation of curcumin for improved oral bioavailability. Biol.
Pharm Bull. 2011;34:660–665.
23. Kanai M, Imaizumi A, Otsuka Y, Sasaki H, Hashiguchi M, Tsujiko K,
Matsumoto S, Ishiguro H, Chiba T. Dose-escalation and pharmacoki-
netic study of nanoparticle curcumin, a potential anticancer agent
with improved bioavailability, in healthy human volunteers. Cancer
Chemother Pharmacol. 2012;69:65–70.
8 S. J. STOHS ET AL.
Downloaded by [47.184.199.61] at 08:52 18 October 2017
24. Kanai M, Otsuka Y, Otsuka K, Sato M, Nishimura T, Mori Y, Kawagu-
chi M, Hatano E, Kodama Y, Matsumoto S, et al. A phase I study
investigation the safety and pharmacokinetics of highly bioavailable
curcumin (Theracurmin) in cancer patients. Cancer Chemother Phar-
macol. 2013;71:1521–1539.
25. Asher GN, Xie Y, Moaddel R, Sanghvi M, Sossou KSS, Kashuba ADM,
Sandler RS, Hawke RL. Randomized pharmacokinetic crossover study
comparing 2 curcumin preparations in plasma and rectal tissue of
healthy human volunteers. J Clin Pharmacol. 2017;57:185–191.
26. Antony B, Merina B, Iyer VS, Judy N, Lennartz K, Joyal S. A pilot
cross-over study to evaluate human oral bioavailability of BCM-
95ÒCG (BiocurcumaxTM), a novel bioenhanced preparation of curcu-
min. Indian J Pharm Sci. 2008;70:445–449.
27. Sunagawa Y, Hirano S, Katanaska Y, Miyazaki Y, Funamoto M,
Ksamura N, Hojo Y, Sukuki J, Doi O, Yokoji T, et al. Colloidal submi-
cron-particle curcumin exhibits high absorption efficiency: a double-
blind, 3-way crossover study. J Nutr Sci Vitaminol. 2015;61:37–44.
28. Morimoto T, Sunagawa Y, Katanassaka Y, Hiraon S, Namiki M, Wata-
nabe Y, Suzuki H, Doi O, Suzuki K, Yamauchi M, et al. Drinkable
preparation of Theracurmin exhibits high absorption efficiency—a
single-dose, double-blind, 4-way crossover study. Biol Pharm Bull.
2013;36:1708–1714.
29. Jager R, Lowrey RP, Calvanese AV, Joy JM, Purpura M, Wilson JM.
Comparative absorption of curcumin formulations. Nutr J. 2014;13;
doi:10.1186/1475-2891-13-11.
30. Gota VS, Maru GB, Soni TG, Gandhi TR, Kochar N, Agarwal MG.
Safety and pharmacokinetics of a solid lipid curcumin particle formu-
lation in osteosarcoma patients and healthy volunteers. Agric Food
Chem. 2010;58:2095–2099.
31. Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown
MJ, Togni S, Dixon BM. Comparative absorption of a standardized
curcuminoid mixture and its lecithin formulation. J Nat Prod.
2011;74:664–669.
32. Purpura M, Lowrey RP, Wilson JM, Mannan H, Munch G, Razmov-
ski-Maumovski V. Analysis of different innovative formulations of
curcumin for improved relative oral bioavailability in human subjects.
Eur J Nutr. 2017; doi:10.1007/s00394-016-1376-9.
33. Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson
MM, Pirmohamed M, Marnett LJ, Grescher AJ, Steward WP. Pharma-
codynamic and pharmacokinetic study of oral curcumin extract in
patients with colorectal cancer. Clin Cancer Res. 2001;7:1894–1900.
34. Garcea G, Jones DJ, Singh R, Dennison AR, Farmer PB, Sharma RA,
Steward WP, Gescher AJ, Berry DP. Detection of curcumin and its
metabolites in hepatic tissue and portal blood of patients following
oral administration. Br J Cancer. 2004;90:1101–1015.
35. Garcea G, Berry DP, Jones DJ, Singh R, Dennison AR, Farmer PB,
Sharma RA, Steward WP, Gescher AJ. Consumption of the putative
chemopreventive agent curcumin by cancer patients: assessment of
curcumin levels in the colorectum and their pharmacodynamics con-
sequences. Cancer Epidemiol Biomarkers Prev. 2005;14:120–125.
36. Cao Y, Xu RX, Liu Z. A high throughput quantification of curcumi-
noids and their curcumin metabolites in human plasma via high-per-
formance liquid chromatography/tandem mass spectrometry. J
Chromatog B Analyt Technol Biomed Life Sci. 2014;949–950:70–78.
37. Asher GN, Xie Y, Moaddel R, Sanghvi M, Diossou KS, Kashuba
AD, Sandler RS, Hawke RL. Randomized pharmacokinetic cross-
over study comparing 2 curcumin preparations in plasma and rec-
tal tissue of healthy human volunteers. J Clin Pharmacol.
2017;57:185–193.
38. Klickovic U, Doberer D, Gouya G, Aschauer S, Weisshaar S, Storka A,
Bilban M, Wolzt M. Human pharmacokinetics of high dose oral cur-
cumin and its effect on heme oxygenase-1 expression in healthy male
subjects. BioMed Res Int. 2014; doi:10.1155/2014/458592.
39. Chen AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT,
Lin BR, Ming-Shiang W, et al. Phase I clinical trial of curcumin, a che-
moprotective agent, in patients with high-risk or pre-malignant
lesions. Anticancer Res. 2001;21:2895–2900.
40. Gopi S, George R, Thomas M, Jude S. A pilot cross-over study to
assess the human bio-availability of “Cureit”a bioavailable curcumin
in complex natural matrix. Asian Journal of Pharmaceutical Technol-
ogy and Innovation. 2015;3:92–96.
41. Vareed SK, Kakarala M, Ruffin MT, Crowell JA, Normolle DP, Djuric
Z, Brenner DE. Pharmacokinetics of curcumin conjugate metabolites
in healthy human subjects. Cancer Epidemiol Biomarkers Prev.
2008;17:1411–1417.
42. BegumAN,JonesMR,LimGP,MoriharaT,KimP,HeathDD,
Rock CL, Pruitt MA, Yang F, Hudspeth B, et al. Curcumin struc-
ture–function, bioavailability and efficacy in models of neuro-
inflammation and Alzheimer’s disease. J Pharmacol Exp Ther.
2008;326:196–208.
43. Sandur SK, Pandey MK, Sung B, Ahn KS, Murakami A, Sethi G,
Limtrakul P, Badmaev V, Aggarwal BB. Curcumin, demethoxycur-
cumin, bisdemethoxycurcumin tetrahydrocurcumin and turmer-
ones differentially regulate anti-inflammatory and anti-
proliferative responses through a ROS independent mechanism.
Carcinogenesis. 2007;28:1765–1773.
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