850
Cancer Epidemiology, Biomarkers & Prevention
Single-Dose Pharmacokinetic Study of Lycopene
Delivered in a Well-Defined Food-Based Lycopene
Delivery System (Tomato Paste-Oil Mixture)
in Healthy Adult Male Subjects
David M. Gustin,1 Keith A. Rodvold,2 Jeffery A. Sosman,6 Veda Diwadkar-Navsariwala,3
Maria Stacewicz-Sapuntzakis,3 Marlos Viana,4 James A. Crowell,7 Judith Murray,5 Patricia Tiller,5
and Phyllis E. Bowen3
1
Division of Hematology-Oncology, Department of Medicine, University of Chicago, Chicago, Illinois; 2Department of Pharmacy Practice,
College of Pharmacy, 3Department of Human Nutrition, 4Departments of Ophthalmology and Visual Sciences, and 5Division of HematologyOncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; 6Division of Hematology-Oncology, Department of
Medicine, Vanderbilt University, Nashville, Tennessee; and 7Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland
Abstract
This report details the findings of a single-dose Phase I
pharmacokinetic and toxicity study of a food-based
formulation of lycopene in healthy adult male subjects.
Five dosing groups (n = 5 per group) were sequentially
treated with increasing doses of lycopene ranging from 10
to 120 mg. Blood samples were collected for a total
of 28 days (672 h) after administration of single doses
of lycopene. The mean time (t max) to reach maximum total
lycopene concentration (C max) ranged from 15.6 to 32.6 h.
The C max for total lycopene ranged between 4.03 and 11.27
Mg/dl (0.075 – 0.210 MM). Mean AUC0 – 96 and elimination
half-life for total lycopene ranged from 214 to 655 Mg h/dl
(3.986 – 12.201 Mmol h/l) and 28.1 and 61.6 h, respectively.
The changes observed in lycopene exposure parameters
(e.g., C max and AUC0 – 96) were not proportional to incre-
ments in dose, with larger increases observed at the
lowest end of the dosing range (10 – 30 mg). Chylomicron
lycopene was measured during the first 12 h with the
differences observed among the dosing groups not
reaching statistical significance. These findings may
reflect a process of absorption that is saturable at very
low dosing levels or may be explained by the large
interindividual variability in attained lycopene concentrations that were observed within each dosing group.
Pharmacokinetic parameters for trans- and cis-lycopene
isomers were calculated and are reported here. The
formulation was well tolerated with minimal side effects, which were mainly of gastrointestinal nature and
of very low grade. (Cancer Epidemiol Biomarkers Prev
2004;13(5):850 – 60)
Introduction
Epidemiological evidence suggests that high consumption of vegetables and fruits is associated with a reduced
risk of cancer (1). High levels of oxidative stress may
result in damage to tissue macromolecules (i.e., DNA,
proteins, lipids) and the development of chronic illnesses
such as cancer and cardiovascular disease (2 – 4). Natural
antioxidants, especially the carotenoids, are present in
fruits and vegetables and may mediate the protective
anticancer effects suggested by the epidemiological and
ecological studies. By far, h-carotene has been the most
studied of all carotenoids (5). Despite overwhelming
epidemiological information linking consumption of
h-carotene with lung cancer protection, large intervention
studies disproved a beneficial role for h-carotene in pre-
Received 10/9/03; revised 12/2/03; accepted 1/8/04.
Grant support: National Cancer Institute, Division of Cancer Prevention, contract
(NO1-CN-85081-70), and by the General Clinical Research Center at the University
of Illinois at Chicago, which is funded by NIH grant M01-RR-13987.
The costs of publication of this article were defrayed in part by the payment of
page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Keith A. Rodvold, m/c 886, College of Pharmacy, University
of Illinois at Chicago, 833 South Wood Street, Room #164, Chicago, IL 60612.
Phone: (312) 996-3341; Fax: (312) 413-1797. E-mail: [email protected]
venting human lung carcinogenesis, with some of the
data suggesting a possible deleterious effect (6, 7). These
unexpected results propelled the scientific inquiry toward the elucidation of the possible role of other natural
antioxidants, beyond h-carotene.
Lycopene is the most prevalent carotenoid present in
the human serum of Americans, accounting for roughly
50% of all plasma carotenoid content (8). Most of the
dietary lycopene consumed by populations in the
western world comes from tomatoes or their products
(9, 10). Epidemiological studies looking at cancer
protection on the basis of patterns of tomato consumption have yielded controversial results, with some but not
all demonstrating a protective effect. Variability in
lycopene bioavailability from different tomato products
may explain these mixed results. This assertion is
supported by the consistent protective effect of lycopene
in epidemiological studies that have explored associations between serum lycopene concentrations and cancer
risk as opposed to dietary patterns of tomato consumption (10). Published reports have confirmed that significant differences exist between different tomato products
in terms of lycopene release and its gastrointestinal
absorption (11 – 14). Of the commonly consumed tomato
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
Cancer Epidemiology, Biomarkers & Prevention
products, tomato paste compares favorably to fresh
tomatoes and/or tomato juice (11, 15). Lycopene is a
very hydrophobic molecule located within the tomato
fruit matrix (16). Mechanical treatment (homogenization)
and heating enhance the release of lycopene from the
tomato matrix and may explain the improved bioavailability seen with consumption of processed tomato
products (cooked tomatoes, tomato paste) (17). The
presence of fat in the diet may also favorably affect the
absorption of lycopene (18). These factors need to be
taken into consideration when devising a dietary
intervention for lycopene delivery or when comparing
pharmacological data obtained from the use of different
food-based interventions.
The putative anticancer effects of lycopene may be
mediated by its extraordinary antioxidant properties (8).
In fact, lycopene displays the highest singlet oxygen
quenching ability among the most common carotenoids,
thus providing the highest protection against oxidative
damage (8, 19). Other plausible (non-antioxidant) mechanisms include the modulation of gap-junctional cell
communication (19), inhibition of growth and induction
of differentiation (19, 20), modulation of the insulin-like
growth factor I (IGF-I)/IGFBP-3 system (21, 22) and modulation of enzymatic systems in charge of carcinogen
metabolism (23, 24). Furthermore, lycopene displays
strong inhibitory effects in experiments using a variety
of human-derived cancer cells (21, 25). A number of
short-term intervention studies using different formulations of lycopene have been reported in the literature
(11, 26 – 30). However, with the exception of a handful
bioavailability reports using short-term sampling strategies and a few short-term intervention studies with
sparing sampling, limited information describing the
human pharmacology of lycopene in detail have been
published (31).
This report details the findings of a single-dose
escalation study of lycopene delivered in a well-standardized food delivery system to healthy male volunteers. This Phase I clinical study was designed to provide
detailed information (28-day sampling period) of the
pharmacokinetic parameters of lycopene and its isomers
after single-dose administration within the 10 – 120 mg
dose range. We also describe the toxicity profile and
report on the oral absorption of this formulation, through
the evaluation of chylomicron-bound lycopene sampled
at prespecified time points during the first 12 h postadministration.
Subjects and Methods
Subject Selection. This study was open to healthy
male volunteers, ages 18 – 45, who at the time of
enrollment were not using prescription medications,
without history of alcohol use (72 h or more), and were
not current smokers (should have quit at least 3 months
before study entry). Because the most obvious future
application of lycopene is for the chemoprevention of
prostate carcinogenesis, we decided to focus our Phase I
efforts on male subjects. Individuals were eligible if
judged to be in good medical condition based on history
and physical exam confirming the absence of chronic
medical diseases or the use of regular prescription
medications, lack of evidence for a psychiatric disorder,
and performance status of 100% in the Karnofsky scale.
Additional eligibility requirements included proof of
normal organ function evidenced by liver and kidney
function tests falling within the institutional normal values, as well as acceptable hematological function defined
by WBC counts z4.0 K/Al, hemoglobin z13.5 g/dl, and
platelet counts within normal institutional range.
Subjects had to be within 15% of ideal body weight
based on standard weight tables and display pre-study
lycopene concentrations <700 nM. Pilot single-dose
studies conducted by our group in an unscreened
population revealed that very little change in total blood
lycopene concentrations were elicited in subjects with
relatively high baseline plasma concentrations at low
dosing levels (V30 mg).8 To maximize our ability to
identify changes in plasma lycopene concentrations after
the administration of only a single dose, it was decided to
screen out subjects with relatively high baseline concentrations (z700 nM).
Individuals unable to provide informed consent were
ineligible. Additional exclusion criteria included history
of gastrointestinal malabsorption (or other condition
that could affect drug absorption), use of a prescription
drug within the 14 days preceding study entry, and
allergy to tomato-based products. Subjects were excluded if they were participating in another experimental
trial where drug intake would have ended less than 4
weeks before study entry. Additionally, the presence of
a health condition that in the judgment of the investigator could pose a threat to the subject’s life and
an abnormal electrocardiogram (EKG) made subjects
ineligible.
Pre-Study Procedures and Evaluations. Pre-screening
telephone interviews were conducted where age, gender,
smoking status, health status, alcohol use, and current
medication use were ascertained. Individuals preliminarily meeting eligibility criteria were invited for a pre-study
evaluation visit. Subjects were consented for participation, a blood sample was drawn to determine a baseline
lycopene concentration, and a diet history was obtained.
During this visit, all the evaluations necessary to
determine eligibility were scheduled and research subjects reviewed and signed the informed consent. Eligible
individuals were then registered onto the study.
At the time of registration, participants were assigned
to a specific dose level of lycopene, which was designated
in sequence depending on toxicity and last dose level
filled. We proceeded with escalation to the next dose level
when at most one in five patients developed grade 2 or
higher toxicity. Accrual to the next dose level only began
after all five patients had completed the preceding dose.
The maximum tolerated dose (MTD) was predefined as
the dose of lycopene below the level where at least two
patients developed grade 2 toxicity or even a single
patient developed grade 3 or 4 toxicity which was
definitely drug related.
On-Study Procedures and Evaluations. On the day of
lycopene dosing, subjects were admitted to the General
Clinical Research Center at the University of Illinois at
8
P.E. Bowen, personal communication.
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
851
852
Pharmacokinetics of Food-Based Lycopene
Chicago (CRC), where a medical history, physical exam
(PE) including vital signs and review of symptoms were
obtained. Weight (Wt) and body surface area (BSA) were
also measured. An angiocatheter was placed for IV access
and blood drawing. Subjects were instructed to come to
the CRC in a fasting state. After baseline blood studies
were drawn, the appropriate dose of lycopene was
administered p.o. with up to 250 ml of water over a
maximum period of 15 min. Immediately after the
appropriate dose of lycopene had been ingested, the
subjects were asked to consume a negligible carotenoidcontaining breakfast which provided 30% of the calories
as fat and constituting 20% of the subjects energy needs
for the day. Lunch was fed immediately after the 4-h draw
and dinner after the 8-h draw. These meals contained
negligible carotenoid content and 30% of calories as fat.
Lunch provided 30% and dinner 40% of each subject’s
energy requirement. This energy distribution typifies the
usual energy distribution in the American diet. The same
meals were fed to the subjects on the second day of the
study. When subjects were discharged from the CRC,
they were seen by the nutritionist and instructed to follow a low carotenoid-eating plan until the completion of
the study.
After lycopene administration, the subjects remained in the CRC for up to a maximum of 36 h and had
hourly vital signs monitored for the initial 4 h.
Thereafter, vital signs were taken once per day by the
CRC nurses for the 2 days of the admission. A
traditional intensive sampling strategy was used with
7 ml blood samples collected before [time zero (0)] and
at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 168, 240,
336, 408, 504, 576, and 672 h after lycopene administration. The intense sampling during the first 12 h assisted
in the determination of the concentration-time profile of
chylomicron lycopene for the assessment of lycopene
absorption. The extensive blood sampling up to 672 h (28
days) was used to characterize the potential long
elimination phase of lycopene. Blood collected at each
sampling time point (0 – 672 h) was assayed for concentrations of total lycopene as well as its cis and trans
isomers. In addition, samples collected during the initial
12 h were also assayed for chylomicron distribution
of lycopene, as a measure of lycopene gastrointestinal
absorption.
Treatment Plan. The basic formulation for the tomato
juice consisted of 30 g of tomato paste incorporated into
5 ml of olive oil. This mixture was then mixed into a
smooth paste and then made to 100 ml volume with
purified water and blended again to give a smooth
consistent juice mixture. The addition of olive oil had the
purpose of improving lycopene bioavailability and of
making the formula more palatable. The formula was
homogenized in a blender to provide a uniform texture
and to help improve lycopene bioavailability by releasing
it from its matrix. Different batches of tomato paste may
vary in their lycopene content. For this reason, every
batch was analyzed for lycopene content and standardized to the all-trans isomer. The distribution of lycopene
isomers in the formulation was 88% all-trans isomer, 8%
cis isomer-1, and 4% for cis isomers-2, -3, and -4. The total
volume of the formulation administered to a given
research subject (within a specific dosing level) was
adjusted to reflect this variability in lycopene content
from batch to batch of tomato paste, so that the intended
total dose of lycopene was delivered. The following
dosing levels were evaluated: 10, 30, 60, 90, and 120 mg.
These dosing levels corresponded to the following
volumes of administration: 79 ml (10 mg), 238 ml
(30 mg), 476 ml (60 mg), 769 ml (90mg), and 797 ml
(120 mg). Research subjects were assigned to a treatment
level, in the order in which they were identified during
the enrollment period. Once a treatment level was
completed, a safety assessment was undertaken and if
no dose-limiting toxicity had occurred, we would open
the immediate higher dosing level for accrual.
Assessment of Toxicity. Toxicity evaluations were
conducted in person at 12 h, 24 h, 48 h, 1 week, 2 weeks,
3 weeks, and 4 weeks after lycopene administration.
Complete blood cell counts including platelets were
obtained pre-study, 1 weeks, and 4 weeks after lycopene
administration. Chemistry panel, cholesterol, triglycerides, and cholesterol fractions (high-density lipoprotein,
low-density lipoprotein, and very low-density lipoprotein) were assessed during the pre-study visit and at
12 h, 1 week, and 4 weeks after lycopene administration.
Adverse events were graded by a numerical score according to a defined Toxicity Grading Scale (NCI’s
Common Toxicity Criteria Version 2.0).
Dietary Considerations. As lycopene is very lipophilic
and is absorbed ‘‘packaged’’ into chylomicrons, the
meals during the first 36 h of the study (CRC inpatient
stay) were designed to be sufficiently fat-rich as to
enhance lycopene absorption (see above). All meals were
lycopene deplete. Subjects were instructed to avoid
lycopene-containing foodstuffs throughout the duration
of the study (28 days). Dietary assessments were
conducted at prespecified time points throughout the
study to document compliance with dietary restrictions.
Compliance and Evaluability. During the consumption of the study formulation, participants were carefully
observed so that the intended volume of the food-based
delivery system was fully consumed. The following time
schedule was designed to define compliance with blood
draws. In this system, some leeway was allowed in
obtaining blood concentrations as follows: (a) During the
CRC stay (first 36 h): 15-min leeway for samples obtained
from 0 to 12 h and 30-min leeway for samples obtained
from 24 to 36 h. (b) During follow-up visits (48 – 672 h):
12-h leeway for samples from 48 to 96 h and 24-h leeway
for samples from 168 to 672 h. To consider a participant
evaluable for analysis, the participant should have
ingested all study drug over the indicated maximum
period of time (15 min) and should have at least
complied with 18 of the 23 (circa 75%) scheduled blood
draws for determining lycopene concentrations.
Analytic Methodology for Assaying Lycopene and
Isomers in Biological and Food Samples. Analysis of fatsoluble vitamins and carotenoids in serum was performed following methodology described previously
(32). Briefly, 200 Al of serum are mixed with 200 Al
ethanol containing retinyl acetate as an internal standard,
and extracted twice with 2 ml hexane (containing 0.01%
BHT to prevent oxidation). The combined hexane layers
are evaporated to dryness under reduced pressure
(Speed-Vac centrifuge) and the residue reconstituted to
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
Cancer Epidemiology, Biomarkers & Prevention
the original serum volume of 200 Al with 50 Al stabilized ethyl ether and 150 Al mobile phase (methanol:acetonitrile:stabilized tetrahydrofuran, 50:45:5, v/v/v)
for subsequent high-performance liquid chromatography (HPLC) isocratic separation on Novapac C18
reverse-phase column. The peaks were detected by
Waters 490 Programmable Multiwavelength Detector
with four channels, each analyte at its specific maximum absorbance (325 nm for vitamin A compounds,
295 nm for vitamin E compounds, 450 nm for carotenoids other than lycopene, 472 nm for lycopene).
Lycopene isomers were separated using a Suplex pKb100 C18 column with methanol:acetonitrile:isopropanol
(54:44:2, v/v/v) isocratic elution according to previously published methodology (33). Extraction and
analysis of fat-soluble vitamins and carotenoids in
foods was undertaken according to methods previously
described by our laboratory (34). The limit of detection
of lycopene for this method is 0.5 Ag/dl (or 10 nM).
The variability of the assay is 2.7% (within-day) and
7.4% (between-day).
Separation of Chylomicrons from Serum Samples.
Chylomicrons were separated according to a method
described by Borel et al. (35). Briefly, 2 ml of postprandial
serum sample are carefully layered under 4 ml of 0.9%
NaCl solution and centrifuged in a high-performance
centrifuge (Avanti J series) at 90,000 g for 1 h in a JA
30.5 fixed angle rotor. This method for chylomicron
separation has been adapted from the original method
described by Dole and Hamlin (36) and Grundy and Mok
(37). After isolation, analysis for total lycopene and
isomers proceeded according to analytical methodology
described above.
Pharmacokinetic Analysis. Pharmacokinetic analysis
was performed on plasma concentration-time data of 25
healthy male subjects. The plasma-concentration time
data included measurements of total, trans-, and cislycopene concentrations from hours zero (0) until 672 h
following lycopene administration. In addition, plasma
concentration-time data included measurements of chylomicron concentrations of total, trans-, and cis-lycopene
from hours zero (0) until 12 h following lycopene
administration. The concentration-time data from each
matrix was corrected by subtracting the plasma lycopene
concentration at time zero (baseline) before the pharmacokinetic analysis of the data was performed. Only
concentrations with a positive value were used in
pharmacokinetic analysis.
Total Lycopene Concentrations. Noncompartmental
pharmacokinetic parameters were estimated using the
microcomputer program, WinNONLIN (version 1.1,
Scientific Consulting, Inc., Apex, NC). Peak plasma
concentration (C max) and the time of C max (t max) were
determined directly from the individual observed lycopene concentration-time data. Area under the concentration-time curve from time zero (0) to 96 h (AUC0 – 96) or to
the last measured time point (AUC0 – last Cp) were
determined by the log-linear trapezoidal rule. The area
term was extrapolated to infinity (AUC0 – 1) using the
elimination rate constant (k el). Elimination rate constant
(k el) was obtained by nonlinear iterative least squares
regression of the terminal log-linear portion of the concentration-time curve. The elimination half-life (t 1/2h)
was calculated by dividing k el into the natural logarithm
of 2. The apparent clearance (CL/F) and volume of
distribution (V h/F) were calculated from the following
equations:
CL=F ¼ Doseoral =AUC01
Vh =F ¼ Doseoral =AUC01 kel
where F is the fraction of bioavailability and assumed
to be 1.
Trans- and Cis-Lycopene Concentrations. Noncompartmental pharmacokinetic parameters were also estimated using WinNONLIN. Peak plasma concentration
(C max) and the time of C max (t max) were determined
directly from the individual observed trans- and cislycopene concentration-time data. Area under the concentration-time curve from time zero (0) to 96 h (AUC0 – 96)
or to the last measured time point (AUC0 – last Cp) was
determined by the log-linear trapezoidal rule.
Chylomicron Lycopene Concentrations. Noncompartmental pharmacokinetic parameters were estimated
using WinNONLIN. Peak plasma concentration (C max)
and the time of C max (t max) were determined directly
from the individual observed total, trans-, and cislycopene concentration-time data. Area under the concentration-time curve from time zero (0) to 12 h (AUC0 – 12)
was determined by the log-linear trapezoidal rule.
Statistical Analysis. Overall differences in subject
characteristics and pharmacokinetic parameters of systemic exposure (e.g., C max and AUC) across the five
different dosing regimens were evaluated by KruskalWallis ANOVA. When significant differences were
found, individual differences between different dosing
regimens were evaluated by a Bonferroni’s t test.
Significance was determined at the P < 0.05 level.
Results
Subject Characteristics. Ninety-three individuals
were screened by telephone. Thirty-four of these individuals underwent a pre-study evaluation and 27 were
ultimately enrolled. Twenty-five subjects were evaluable
due to two participants dropping out before study
initiation. Minor exceptions were made by the principal
investigator, which permitted the enrollment of two
subjects. One subject had a BUN value (21 mg/dl) that
was minimally higher than the required upper limit of
normal (20 mg/dl). Another subject was also allowed to
participate with a WBC count (4.7 K/Al) just under the
required normal institutional value (4.8 K/Al). No other
exceptions were made. One eligibility violation was
committed when an individual with a baseline hemoglobin of 13.1 g/dl (13.5 g/dl required) was entered into
the study. His hemoglobin concentration had risen to
13.5 g/dl 7 days into the study, which is within eligibility
range. The eligibility criteria were revised twice as
follows: (a) WBC count and hemoglobin concentration
that allowed participation were changed from the
‘‘upper limit of normality for the institution’’ to
z4.0 K/Al and z13.5 g/dl, respectively, and (b) the
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
853
854
Pharmacokinetics of Food-Based Lycopene
pre-study lycopene concentration that would allow
participation was increased to 700 nM (from 600 nM).
These changes in eligibility were implemented to
facilitate and expedite accrual into the study. Table 1
summarizes the baseline characteristics for each group.
No major differences were observed between the groups.
Safety and Toxicity. All 25 participants received the
intended treatment according to the assigned dose
concentration. Five subjects were assigned to each dosing
level (10, 30, 60, 90 and 120 mg), and received a single
dose of lycopene through a well-characterized foodbased formulation. All treated subjects were included in
the safety analysis. The two subjects that were enrolled in
the study but withdrew were not included in the analysis
as neither of them consumed lycopene. Overall the
formulation was well tolerated after single oral administration. No significant toxicity (>grade 2) was observed
that could be linked to lycopene ingestion. The most
common adverse events that were observed included
headaches (7 of 25), nausea (6 of 25), and diarrhea (4 of
25). Of these, only two episodes of nausea and two of
diarrhea were felt to be related or possibly related to the
study drug, and were of low grade (grade 1). Three
days after ingesting lycopene, one of the participants
sustained a skin laceration with a metal object in the
medial aspect of his left leg, which was subsequently
infected and required hospitalization for antibiotics.
During the course of antibiotic treatment, he developed
a skin rash and was deemed to have an allergic reaction
to the antibiotics. The participant fully recovered from
this unrelated event and completed all study requirements and evaluations without toxicity attributable to
lycopene. No changes were seen on physical exam from
baseline. Five subjects displayed ‘‘grade 1’’ leukopenia
(defined as WBC counts between 3.0 and 3.9). It is
important to mention that in most of these subjects,
their baseline WBC count was close to 4.0. These
abnormalities were for the most part seen at the 28day blood draw, and could not be linked with absolute
certainty to lycopene ingestion. No significant changes
in hemoglobin were seen. Only one subject in the study
(90 mg dose level) experienced a decrease in platelet
values. This subject had a baseline platelet count of
179,000, his day 7 platelet count was 176,000, and on
day 28, he displayed a minimally decreased platelet
count of 143,000. The relatedness of this event to
lycopene intake is unclear. Minimal changes in blood
chemistry parameters were seen which were felt not
related to lycopene. No significant hepatic or renal
toxicity attributable to lycopene was seen. No relationships were found between lycopene concentrations and
toxicities that were observed.
Pharmacokinetics. The mean F SD of the plasma
concentrations of total, trans-, and cis- lycopene for the
five dosing levels are shown in Fig. 1. These plates
illustrate the plasma concentrations between hours 0
and 672 h (inserted figure) as well as the change in
baseline concentrations between hours 0 and 96 h.
Table 2 summarizes the pharmacokinetic parameters for
total lycopene at each dose level. After administration of
single oral doses of lycopene, the mean time (t max) to
reach maximum total lycopene concentration (C max)
ranged from 15.6 to 32.6 h. Mean maximal concentration
(C max) for total lycopene ranged between 4.03 and
11.27 Ag/dl (0.075 – 0.120 AM). Mean AUC0 – 96 for total
lycopene ranged from 214 to 655 Ag h/dl (3.986 – 12.201
Amol h/l). The mean half-life for total lycopene ranged
between 28.1 and 61.6 h. The ranges for the mean values
of apparent CL/F and V h/F included 98.6 –286.4 ml/min
and 2.12 – 18.54 l/kg, respectively.
Table 3 summarizes the pharmacokinetic parameters
for lycopene isomers for each dose level. The ranges of
mean t max for trans and cis isomers of lycopene were
17.8 – 34.0 h and 22.5 – 56.0 h, respectively. Mean values
for C max and AUC0 – 96 of the trans isomer tended to
increase with ascending oral doses. The mean values
of C max for the cis isomer were of similar magnitude
for dose levels between 30 and 120 mg. Similar to what
was seen with total lycopene, the mean AUC0 – 96 and
C max for the cis isomers were similar at dose levels of
30 and 60 mg, and at 90 and 120 mg. Isomer
distribution of trans- and cis-lycopene (expressed by
the trans/cis lycopene AUC0 – 96 ratio) ranged from 1.47
to 1.76, and no major differences were observed
between the ascending oral doses (data not shown).
The trans isomer accounted for 54 – 65% of the mean
AUC0 – 96 of total lycopene, whereas cis isomer ranged
from 36% to 41%.
Figure 2 displays a series of scatter plots of C max
achieved by total lycopene and isomers versus dose
levels. This figure suggests that most of the gain in C max
after single-dose administration is realized in the lower
range of the dosing interval (between 10 and 30 mg).
Figure 3 is a series of scatter plots displaying AUCs for
total lycopene and isomers versus dosing level. Similar
to what was seen for C max, the maximum increase in
Table 1. Baseline characteristics of the 25 study subjects
Dose level
10 mg
Age (years)
Weight (kg)
Height (cm)
BMI (kg/m2)
Lycopene (AM)
Triglycerides (mg/dl)
Cholesterol (mg/dl)
25.8
79.1
179.1
24.5
0.426
128
167
30 mg
F
F
F
F
F
F
F
4.6
11.8
8.7
1.8
0.032
93
30
26.0
74.1
177.8
24.1
0.490
82
168
F
F
F
F
F
F
F
60 mg
4.7
5.4
7.8
2.7
0.110
50
32
30.4
76.3
176.4
24.4
0.536
123
175
F
F
F
F
F
F
F
90 mg
4.5
13.1
7.4
2.6
0.101
76
15
22.6
69.5
176.0
22.5
0.459
92
177
F
F
F
F
F
F
F
120 mg
4.4
3.3
2.7
1.2
0.083
50
37
30.2
79.7
180.1
24.5
0.546
85
166
F
F
F
F
F
F
F
Note: Data are expressed as mean F SD.
BMI, body mass index.
The differences in patient characteristics were not significant (P > 0.05) among the five dose regimens.
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
8.5
11.5
5.2
3.0
0.105
30
30
Cancer Epidemiology, Biomarkers & Prevention
Figure 1. Mean (FSD) change in plasma concentrations for lycopene
(closed circles), trans-lycopene (shaded triangles ), and cis -lycopene
(open diamonds ) for the first 96 h after a single dose of 10 mg (A),
30 mg (B), 60 mg (C), 90 mg (D), and 120 mg (E). The insets show
the mean (FSD) plasma concentration-versus -time profile of lycopene,
trans -lycopene, and cis -lycopene.
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
855
856
Pharmacokinetics of Food-Based Lycopene
Table 2. Noncompartmental pharmacokinetic parameters for total lycopene
10 mg
C max (Ag/dl)
C max (AM)
t max (h)
AUC0 – 96 h (Ag h/dl)
AUC0 – 96 h (Amol h/l)
AUC0 – 1 (Ag h/dl)
AUC0 – 1 (Amol h/l)
t 1/2 (h)
4.03
0.075
16.6
214
3.99
273.9
5.10
28.1
30 mg
F
F
F
F
F
F
F
F
2.31
0.043
10.1
124.8
2.33
174.1
3.24
23.1
8.76
0.163
19.8
416.4
7.76
450.8
8.40
28.8
60 mg
F
F
F
F
F
F
F
F
2.69
0.050
12.4
183.9
3.43
208.6
3.89
7.4
9.26
0.172
15.6
421.7
7.86
517.3
9.64
36.9
90 mg
F
F
F
F
F
F
F
F
4.19
0.078
13.8
59.3
1.11
38.0
0.71
12.2
10.74
0.200
26.1
598.9
10.99
1047.7
19.52
61.6
120 mg
F
F
F
F
F
F
F
F
5.17*
0.096*
5.5
396.8
7.39
889.1
16.56
37.0
11.27
0.210
32.6
655
12.20
969.8
18.07
40.9
F
F
F
F
F
F
F
F
2.85c
0.053c
18.6
298.6
5.56
621.6
11.58
21.6
Note: Data are expressed as mean F SD.
*Differences between the 90 mg and 10 mg lycopene groups were significant (P < 0.05).
cDifferences between the 120 mg and 10 mg lycopene groups were significant (P < 0.05).
AUC again occurred between 10 and 30 mg. Figure 2
and 3 also reveal the high variability seen for these
parameters among individuals within same dosing
groups.
The noncompartmental pharmacokinetic parameters
estimated from the chylomicron lycopene plasma concentrations are summarized in Table 4. The observed
differences in C max and AUC0 – 12 were not significant
among the five dosing groups for chylomicron-bound
lycopene.
Discussion
Lycopene is a carotenoid and a very potent natural
antioxidant. In the western diet, it is almost exclusively
consumed through the ingestion of fresh tomatoes and
tomato-based products (10, 38). Epidemiological and
experimental studies have suggested strong associations
between lycopene and protection against a variety of
epithelial cancers supporting its clinical development as
a chemopreventive agent (10).
Several pharmacokinetic studies have evaluated the
short-term administration of a number of different
lycopene formulations. The majority of these studies
have only included sparse blood sampling and offer
limited pharmacological detail (11). Intensive blood
sampling schemes have been applied in bioavailability
studies where determinations of chylomicron-bound
lycopene have been measured. However, the focus of
these studies was placed on the first 8 – 12 h after
lycopene administration and dose-response relationships
were not explored (15, 39). Our study was designed to
provide detailed pharmacokinetic information by using a
28-day sampling period and a broad dosing range (12fold) of single doses of lycopene (10 – 120 mg) delivered
in a well-standardized food-delivery system. The lowest
dose of administration used in our study was based on
concentrations of ingestion that in epidemiological
studies have been associated with cancer protection
(10). The highest dose level was defined in response to a
report suggesting that substantial side effects (‘‘lycopenemia’’) may occur with protracted ingestion of very
large amounts of tomato products (40). In addition, the
administration of higher doses (e.g., larger than 120 mg)
of our tomato paste-oil formulation would have not been
feasible given the large volumes of administration that
would be required.
In terms of toxicity, only two episodes of nausea and
two of diarrhea were possibly related to lycopene intake
and were all of mild intensity (grade 1). There was no
consistent association between dose size and lycopenerelated adverse events. Overall, the administration of
single doses of lycopene using our formulation was
feasible and safe. These results are not unexpected given
the wide consumption of tomatoes in the American diet
and are consistent with safety evaluations from previously published reports (41).
As lycopene is naturally present in human plasma, the
pharmacokinetics of lycopene in this study were described in reference to baseline plasma concentrations.
Pharmacokinetic analysis was therefore performed on
the difference between the measured lycopene concentrations at sampled time points minus lycopene concentrations at baseline. The noncompartmental
pharmacokinetic parameters for total lycopene by dosing
group are provided in Table 2. As dietary intake of
Table 3. Noncompartmental pharmacokinetic parameters for lycopene trans- and cis-isomers
Trans-lycopene
10 mg
C max (Ag/dl)
C max (AM)
t max (h)
AUC0 – 96 h (Ag h/dl)
AUC0 – 96 h (Amol h/l)
2.66
0.050
17.8
116.4
2.168
30 mg
F
F
F
F
F
1.31
0.024
8.8
84.2
1.568
5.56
0.104
29.3
237.3
4.420
F
F
F
F
F
60 mg
1.96
0.037
38.7
116.8
2.176
6.13
0.114
34.0
266.2
4.96
F
F
F
F
F
90 mg
3.02
0.056
37.9
61.0
1.136
6.71
0.125
17.8
357.1
6.652
F
F
F
F
F
120 mg
3.26
0.061
9.0
223.9
4.171
6.86
0.128
26.4
425.5
7.926
F
F
F
F
F
1.79
0.033
5.3
150.8*
2.809*
Note: Data are expressed as mean F SD.
*Differences between the 120 mg and 10 mg lycopene groups were significant (P < 0.05).
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
Cancer Epidemiology, Biomarkers & Prevention
Given the high liposolubility of lycopene, its ability to
distribute extensively in peripheral tissues does not come
as a surprise and explains the large total and weightnormalized volumes of distribution that were observed
(e.g., mean V h/F ranging from 160 – 1320 l and 2.12 –
18.54 l/kg).
Time to C max (t max) for chylomicron-lycopene ranged
between 4.2 and 8.4 h, whereas t max for total lycopene occurred roughly after 24 h post-administration
(15.6 – 32.6 h). This temporal pattern is consistent with
that described for other carotenoids and supports the
current physiological notion of lycopene absorption.
Specifically, lycopene is taken up by the enterocyte,
packaged into chylomicrons, and then released into the
portal circulation, a process that take just a few hours
(47 – 49). Chylomicrons are then taken up by the liver and
lycopene is repackaged and released in other kinds of
lipoproteins but predominantly bound to LDL, resulting
in a several-hour delay for total lycopene concentrations
to achieve C max (48, 50, 51). The largest proportion of total
measured lycopene in human plasma is carried in LDL
(51, 52).
In our review of the literature, we were only able to
identify one pharmacokinetic study of lycopene that
included an intensive sampling scheme similar to the one
that we used (31). Porrini et al. (31) administered a single
dose of lycopene to healthy subjects and blood samples
were collected for 104 h after lycopene administration.
However, only one dose level (16.5 mg) was studied. In
this study, peak concentrations (C max) for total lycopene
and isomers were observed earlier than in our study
(6 – 8 h) and may reflect different experimental conditions
including diet and formulation (31). Although t 1/2 was
not reported in that study after single-dose administration, lycopene concentrations returned to baseline between 80 and 104 h, a similar time course to the one
observed in our study (96 h). Systemic exposure
parameters could not be compared as C max were not
reported and AUCs were calculated without subtracting
the baseline lycopene concentration (31).
Contrary to what had been suggested by others, we
were able to elicit changes in total lycopene concentrations after single-dose administration even at the
lowest dosing level (10 mg). In part, this may have been
possible as a consequence of our eligibility criteria which
screened out individuals with high basal lycopene
concentrations (>700 nM), thus providing ample opportunity to identify a concentration change if it occurred. In
addition, our prolonged sampling period may have
allowed us to detect a change in total lycopene which
may be missed in studies using shorter sampling periods.
tomatoes was restricted throughout the duration of the
study, in many subjects, lycopene concentrations fell
below baseline value after 96 h and resulted in negative
values. This is consistent with results reported by Porrini
et al. (31) where a single dose of lycopene (16.5 mg)
resulted in measurable increases in lycopene concentrations with a decline back to baseline at 104 h. For this
reason, we have based our lycopene-exposure commentary on areas under the concentration curves generated
between zero and 96 h (AUC0 – 96 h).
Escalation of lycopene doses resulted in non-proportional increases in pharmacokinetic parameters of systemic drug exposure [e.g., C max and AUC0 – 96 h (Figs. 2 and
and 3)]. These data suggest a sigmoid (versus linear)
distribution of systemic exposure parameters with increasing dosing levels of lycopene. The largest increases
in systemic exposure parameters occurred during dose
escalation at the lower dosing range (10 – 30 mg).
Although the differences between systemic exposure parameters for the 10 and 30 mg groups did not reach
statistical significance, the observed pattern may reflect
saturability during absorption. To better characterize
the pharmacokinetics of fresh lycopene absorption, we
measured and analyzed the changes in chylomicronbound lycopene concentrations during the initial 12
h after dosing. The differences observed among the five
dose regimens for chylomicron-bound total, trans-, or cislycopene were not statistically significant. These findings
may again be consistent with an absorptive process
which may be saturated at very low dosing levels
(<30 mg). Recent information provides indirect evidence
for the presence of transporters that may mediate
carotenoid transfer in mammalian tissues (42, 43).
Although intestinal binding proteins have not been
identified in humans or other mammals, their existence
has been postulated and may be involved in facilitated
and saturable absorption of carotenoids, including
lycopene (44). Alternatively, the changes observed in
C max and AUCs for both total and chylomicron lycopene
may reflect the high interindividual variability in
plasma-lycopene responses observed and the small
sample size used in our study (N = 5 per group). Other
reports have described high interindividual variability in
plasma responses to carotenoids including lycopene (39,
45, 46). An overall concentration ceiling is less likely as
was suggested by the fact that the highest measured
concentrations were observed in the highest dosing
groups (90 and 120 mg). However, with only five
subjects per group, a ceiling concentration cannot be
properly identified with such wide variation in observed
concentrations.
Table 3. Noncompartmental pharmacokinetic parameters for lycopene trans- and cis-isomers (Cont’d)
Cis-lycopene
10 mg
1.86
0.035
20.5
76.9
1.432
F
F
F
F
F
0.91
0.017
7.0
47.6
0.887
30 mg
60 mg
4.29 F 1.23
0.080 F 0.023
34.5 F 37.2
171.3 F 78.1
3.191 F 1.455
3.77
0.070
56
147.3
2.744
F
F
F
F
F
90 mg
1.46
0.027
70.2
40
0.745
4.69
0.087
22.5
243.5
4.536
F
F
F
F
F
120 mg
2.69
0.050
10.7
220.6
4.115
4.71
0.088
28.3
241.7
4.502
F
F
F
F
F
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
1.4
0.026
21.8
141.5
2.636
857
858
Pharmacokinetics of Food-Based Lycopene
The elimination of lycopene has been most extensively
evaluated in carotenoid-withdrawal studies where participants were asked to refrain from ingesting carotenoidrich foodstuffs. Rock et al. (46) estimated the elimination
of a common group of carotenoids in human subjects.
Lycopene displayed the shortest half-life of elimination
after carotenoid withdrawal (12 – 33 days) compared to
other common carotenoids. Most of the decline occurred
during the initial 2 weeks. These results were used to
plan our sampling strategy which extended beyond
2 weeks (total of 4 weeks). Clearly, the results obtained
through carotenoid withdrawal studies are not directly
comparable to the pharmacokinetic parameters generated after single-dose administration. In our study, we
observed an elimination half-life for total lycopene that
ranged between 28.1 and 61.6 h and was shorter than we
originally anticipated. However, these results are consistent with those reported by Porrini et al. (31) where
lycopene plasma concentrations returned to baseline
concentrations at 104 h.
Lycopene is predominantly present in tomatoes and
tomato-derived products (such as ours) in its transisomeric form. At baseline conditions and at steady state,
lycopene is predominantly present in plasma in its cis
configuration. This observation has led to the suggestion
that lycopene’s cis isomers may be preferentially
absorbed from the GI tract. In addition, extensive
isomerization may occur during and/or after absorption.
Research seems to indicate that trans-lycopene has
a higher propensity to precipitate and form crystals
affecting its solubility, a fact that may possibly decrease
its GI absorption relative to the more soluble cis isomers
(53). In our study, we measured both cis and trans
isomers of total as well as chylomicron-contained
lycopene. Although total plasma concentrations of the
cis isomers were higher throughout the duration of the
study, the changes in concentration seen relative to
baseline values were higher for the trans isomer. This
suggests that the trans isomer is absorbed from the GI
lumen and reflects the predominance of this isomeric
form in our formulation (88%). Interestingly, even at
very early sampling times, the proportions of the
different isomers in plasma and in chylomicrons did
not closely resemble the actual proportions in the
formulation. A higher proportion of cis isomers that
would have been expected relative to their concentration
in the formulation was observed. This may be a
consequence of preferential absorption of cis isomers as
previously suggested by other authors and/or in vivo
isomerization during or immediately following absorption. Total lycopene isomeric proportions progressively
returned to ratios that were closer to those observed at
baseline, suggesting continuing lycopene isomerization.
Our study constitutes one of the first detailed
pharmacokinetic evaluations of lycopene using a wellcharacterized and standardized oral food-delivery system. Our findings demonstrate that even small doses of
this compound (10 mg) may induce measurable changes
in plasma concentrations. Although there seems to be
substantial interindividual variability in plasma concentrations after lycopene administration, progressive escalation of lycopene doses results in non-proportional
increases in systemic parameters of exposure (C max and
AUC) with the largest changes seen with dose escalation
at the low end of the dosing range (10 – 30 mg). Therefore,
we anticipate that modest doses of lycopene may result
during chronic administration, in substantial increases in
lycopene blood concentrations, with very limited additional gain achievable with dose escalation beyond
intermediate dosing levels (>30 – 60 mg). The shorter
elimination half-life of lycopene relative to other carotenoids supports its administration on a daily basis. These
assumptions require confirmation through the implementation of well-designed multiple-dose studies. Furthermore, the recommendation of a chronic dose for use
in Phase II studies should be based on the desired target
concentration at steady state and the projected accumulation of lycopene in the target organ. Multiple-dose
Figure 2. Maximum change in plasma concentrations (C max) for lycopene (A), trans -lycopene (B), and
cis -lycopene (C) for the 10, 30, 60,
90, and 120 mg dose.
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
Cancer Epidemiology, Biomarkers & Prevention
Figure 3. Area under the plasma
concentration-time curve during
the first 96 h (AUC0 – 96h) for
lycopene (A), trans -lycopene (B),
and cis -lycopene (C) following a
single dose of 10, 30, 60, 90, and
120 mg of lycopene.
studies are required to provide firm recommendations
in terms of Phase II dosing. These studies would not
only ascertain systemic concentrations of lycopene but
would also measure the concentration in the target
organ as well as the induction of modulation of
relevant biomarkers. Given the large variability observed around any dose level, it is unlikely that one
dose will fit all subjects in terms of inducing similar
systemic exposures. It is possible then that a doseadjusted method may be required. What seems clear at
this point is that further pharmacokinetic studies are
needed which should ideally include larger numbers of
subjects and that would also explore the changes in
systemic exposure of lycopene induced by doses that
fall within the gaps that were not evaluated in this
study (e.g., doses between 10 and 30 mg or between
60 and 90 mg).
Our data suggests that there seem to be three dosing
regions on which differences of exposure are observed:
(a) less than 30 mg; (b) between 30 and 60 mg; and (c)
greater than 60 mg. On the basis of this, our group is
currently conducting a 3-month study of oral lycopene
administration using a similar tomato paste-oil formulation in individuals at high-risk to develop prostate
cancer (e.g., increased PSA concentration) but absence
of invasive malignancies in prostate biopsies. This study
Table 4. Noncompartmental pharmacokinetic parameters for chylomicron-bound lycopene and its isomers
C max
t max (h)
(Ag/dl)
Total lycopene
10 mg
30 mg
60 mg
90 mg
120 mg
Trans-lycopene
10 mg
30 mg
60 mg
90 mg
120 mg
Cis-lycopene
10 mg
30 mg
60 mg
90 mg
120 mg
(AM)
AUC0 – 12
h
(Ag h/dl)
(Amol h/l)
2.572
1.399
2.816
3.248
2.352
F
F
F
F
F
2.590
0.664
1.436
2.262
1.035
0.048
0.026
0.052
0.061
0.044
F
F
F
F
F
0.048
0.012
0.027
0.042
0.019
8.4
4.8
4.5
5.6
4.2
F
F
F
F
F
4.2
3.2
2.4
3.8
0.8
8.65
7.2
16.1
13.52
11.3
F
F
F
F
F
7.21
4.08
9.88
9.67
4.92
0.161
0.134
0.300
0.252
0.210
F
F
F
F
F
0.134
0.076
0.184
0.180
0.092
1.268
0.723
1.794
1.917
1.214
F
F
F
F
F
1.289
0.342
1.036
1.427
0.544
0.024
0.013
0.033
0.036
0.023
F
F
F
F
F
0.024
0.006
0.019
0.027
0.010
7.2
4.8
5.4
5.6
4.2
F
F
F
F
F
3.7
3.2
0.9
3.8
0.8
3.81
3.8
10.38
8.21
6.22
F
F
F
F
F
2.43
2.62
6.70
6.79
2.79
0.071
0.071
0.193
0.153
0.116
F
F
F
F
F
0.045
0.049
0.125
0.126
0.052
1.324
0.704
1.09
1.342
1.138
F
F
F
F
F
1.287
0.359
0.415
0.893
0.512
0.025
0.013
0.020
0.025
0.021
F
F
F
F
F
0.024
0.007
0.008
0.017
0.010
6.6
6.4
4.1
5.4
4.2
F
F
F
F
F
4.2
3.7
2.4
3.9
0.8
4.31
3.6
5.71
4.92
5.78
F
F
F
F
F
3.39
1.39
3.09
3.38
2.38
0.080
0.067
0.106
0.092
0.108
F
F
F
F
F
0.063
0.026
0.058
0.063
0.044
Note: Data are expressed as mean F SD.
The differences in C max and AUC0 – 12 h were not significant (P > 0.05) among the five dose regimens for chylomicron-bound total, trans -, or cis-lycopene.
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
859
860
Pharmacokinetics of Food-Based Lycopene
will explore the multiple-dose pharmacokinetics and
toxicity of lycopene over a dose range of 15 – 78 mg/day.
In addition, this study will explore the concentrations
of lycopene that are achievable in prostate and oral
mucosal tissue at steady state as well as the modulation
of oxidative markers in the blood, mucosa, and prostate.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 1991;2(5):325-57.
Flagg EW, Coates RJ, Greenberg RS. Epidemiologic studies of antioxidants and cancer in humans. J Am Coll Nutr 1995;14(5):419-27.
Kushi LH. Vitamin E and heart disease: a case study. Am J Clin Nutr
1999;69(6):1322S-9S.
Hininger I, Chopra M, Thurnham DI, et al. Effect of increased fruit
and vegetable intake on the susceptibility of lipoprotein to oxidation
in smokers. Eur J Clin Nutr 1997;51(9):601-6.
Johnson EJ. The role of carotenoids in human health. Nutr Clin Care
2002;5(2):56-65.
Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of h carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334(18):1150-5.
Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of longterm supplementation with h carotene on the incidence of malignant
neoplasms and cardiovascular disease. N Engl J Med 1996;334(18):
1145-9.
Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys
1989;274(2):532-8.
Khachik F, Carvalho L, Bernstein PS, et al. Chemistry, distribution,
and metabolism of tomato carotenoids and their impact on human
health. Exp Biol Med (Maywood) 2002;227(10):845-51.
Giovannucci E. Tomatoes, tomato-based products, lycopene, and
cancer: review of the epidemiologic literature. J Natl Cancer Inst
1999;91(4):317-31.
van het Hof KH, de Boer BC, Tijburg LB, et al. Carotenoid
bioavailability in humans from tomatoes processed in different ways
determined from the carotenoid response in the triglyceride-rich
lipoprotein fraction of plasma after a single consumption and in
plasma after four days of consumption. J Nutr 2000;130(5):1189-96.
Shi J, Le Maguer M. Lycopene in tomatoes: chemical and physical
properties affected by food processing. Crit Rev Biotechnol 2000;
20(4):293-334.
Bohm V, Bitsch R. Intestinal absorption of lycopene from different
matrices and interactions to other carotenoids, the lipid status, and the
antioxidant capacity of human plasma. Eur J Nutr 1999;38(3):118-25.
Rao AV, Agarwal S. Bioavailability and in vivo antioxidant properties
of lycopene from tomato products and their possible role in the
prevention of cancer. Nutr Cancer 1998;31(3):199-203.
Gartner C, Stahl W, Sies H. Lycopene is more bioavailable from
tomato paste than from fresh tomatoes. Am J Clin Nutr 1997;66(1):
116-22.
Clinton SK. Lycopene: chemistry, biology, and implications for
human health and disease. Nutr Rev 1998;56(2 Pt 1):35-51.
Nguyen ML, Schwartz SJ. Lycopene stability during food processing.
Proc Soc Exp Biol Med 1998;218(2):101-5.
Clark RM, Yao L, She L, Furr HC. A comparison of lycopene and
astaxanthin absorption from corn oil and olive oil emulsions. Lipids
2000;35(7):803-6.
Livny O, Kaplan I, Reifen R, et al. Lycopene inhibits proliferation and
enhances gap-junction communication of KB-1 human oral tumor
cells. J Nutr 2002;132(12):3754-9.
Heber D, Lu QY. Overview of mechanisms of action of lycopene. Exp
Biol Med (Maywood) 2002;227(10):920-3.
Levy J, Bosin E, Feldman B, et al. Lycopene is a more potent
inhibitor of human cancer cell proliferation than either a-carotene or
h-carotene. Nutr Cancer 1995;24(3):257-66.
Karas M, Amir H, Fishman D, et al. Lycopene interferes with cell
cycle progression and insulin-like growth factor I signaling in
mammary cancer cells. Nutr Cancer 2000;36(1):101-11.
Jewell C, O’Brien NM. Effect of dietary supplementation with
carotenoids on xenobiotic metabolizing enzymes in the liver, lung,
kidney and small intestine of the rat. Br J Nutr 1999;81(3):235-42.
Bhuvaneswari V, Velmurugan B, Nagini S. Induction of glutathionedependent hepatic biotransformation enzymes by lycopene in the
hamster cheek pouch carcinogenesis model. J Biochem Mol Biol
Biophys 2002;6(4):257-60.
25. Kotake-Nara E, Kushiro M, Zhang H, et al. Carotenoids affect proliferation of human prostate cancer cells. J Nutr 2001;131(12):3303-6.
26. Kucuk O, Sarkar FH, Djuric Z, et al. Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol Med
(Maywood) 2002;227(10):881-5.
27. Richelle M, Bortlik K, Liardet S, et al. A food-based formulation
provides lycopene with the same bioavailability to humans as that
from tomato paste. J Nutr 2002;132(3):404-8.
28. Paetau I, Rao D, Wiley ER, et al. Carotenoids in human buccal
mucosa cells after 4 wk of supplementation with tomato juice or
lycopene supplements. Am J Clin Nutr 1999;70(4):490-4.
29. Johnson EJ. Human studies on bioavailability and plasma response
of lycopene. Proc Soc Exp Biol Med 1998;218(2):115-20.
30. Holloway DE, Yang M, Paganga G, et al. Isomerization of dietary
lycopene during assimilation and transport in plasma. Free Radic
Res 2000;32(1):93-102.
31. Porrini M, Riso P, Testolin G. Absorption of lycopene from single
or daily portions of raw and processed tomato. Br J Nutr 1998;80(4):
353-61.
32. Stacewicz-Sapuntzakis M, Bowen PE, Kikendall JW, Burgess M.
Simultaneous determination of serum retinol and various carotenoids: their distribution in middle age men and women. J Micronutr
Anal 1987;3:27-45.
33. Garg V, Bowen PE, Stacewicz-Sapuntzakis M. Serum lycopene response to daily intake of tomato oleoresin. FASEB J 1995;9:A458.
34. Schreiner R, Stacewicz-Sapuntzakis M, Bowen PE, Sawicki M.
Carotenoid analysis of mixed diet aliquots. FASEB J 1992;6:A1657.
35. Borel P, Tyssandier V, Mekki N, et al. Chylomicron h-carotene and
retinyl palmitate responses are dramatically diminished when men
ingest h-carotene with medium-chain rather than long-chain triglycerides. J Nutr 1998;128(8):1361-7.
36. Dole VP, Hamlin JT 3rd. Particulate fat in lymph and blood. Physiol
Rev 1962;42:674-701.
37. Grundy SM, Mok HY. Chylomicron clearance in normal and
hyperlipidemic man. Metabolism 1976;25(11):1225-39.
38. Willcox JK, Catignani GL, Lazarus S. Tomatoes and cardiovascular
health. Crit Rev Food Sci Nutr 2003;43(1):1-18.
39. O’Neill ME, Thurnham DI. Intestinal absorption of h-carotene,
lycopene and lutein in men and women following a standard meal:
response curves in the triacylglycerol-rich lipoprotein fraction. Br J
Nutr 1998;79(2):149-59.
40. Reich P, Shwachman H, Craig JM. Lycopenemia: a variant of
carotenemia. N Engl J Med 1960;262:263-9.
41. Kucuk O, Sarkar FH, Sakr W, et al. Phase II randomized clinical trial
of lycopene supplementation before radical prostatectomy. Cancer
Epidemiol Biomark Prev 2001;10(8):861-8.
42. Tabunoki H, Sugiyama H, Tanaka Y, et al. Isolation, characterization,
and cDNA sequence of a carotenoid binding protein from the silk
gland of Bombyx mori larvae. J Biol Chem 2002;277(35):32133-40.
43. Lakshman MR, Rao MN. Purification and characterization of cellular
carotenoid-binding protein from mammalian liver. Methods Enzymol 1999;299:441-56.
44. Erdman JW Jr, Bierer TL, Gugger ET. Absorption and transport of
carotenoids. Ann NY Acad Sci 1993;691:76-85.
45. Sugerman SB, Mobarhan S, Bowen PE, et al. Serum time curve
characteristics of a fixed dose of h-carotene in young and old men. J
Am Coll Nutr 1991;10(4):297-307.
46. Rock CL, Swendseid ME. Plasma h-carotene response in humans
after meals supplemented with dietary pectin. Am J Clin Nutr 1992;
55(1):96-9.
47. Wingerath T, Stahl W, Sies H. h-Cryptoxanthin selectively increases
in human chylomicrons upon ingestion of tangerine concentrate rich
in h-cryptoxanthin esters. Arch Biochem Biophys 1995;324(2):385-90.
48. Traber MG, Diamond SR, Lane JC, et al. h-Carotene transport in
human lipoproteins. Comparisons with a-tocopherol. Lipids 1994;
29(10):665-9.
49. van Vliet T, Schreurs WH, van den Berg H. Intestinal h-carotene
absorption and cleavage in men: response of h-carotene and retinyl
esters in the triglyceride-rich lipoprotein fraction after a single oral
dose of h-carotene. Am J Clin Nutr 1995;62(1):110-6.
50. Brown ED, Micozzi MS, Craft NE, et al. Plasma carotenoids in normal
men after a single ingestion of vegetables or purified h-carotene. Am
J Clin Nutr 1989;49(6):1258-65.
51. Lin S, Quaroni L, White WS, et al. Localization of carotenoids in
plasma low-density lipoproteins studied by surface-enhanced resonance Raman spectroscopy. Biopolymers 2000;57(4):249-56.
52. Lowe GM, Bilton RF, Young AJ, et al. Carotenoid profiles of human
plasma lipoproteins. Biochem Soc Trans 1996;24(2):171S.
53. Britton G. Structure and properties of carotenoids in relation to
function. FASEB J 1995;9(15):1551-8.
Cancer Epidemiol Biomarkers Prev 2004;13(5). May 2004
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.
Single-Dose Pharmacokinetic Study of Lycopene Delivered
in a Well-Defined Food-Based Lycopene Delivery System
(Tomato Paste-Oil Mixture) in Healthy Adult Male Subjects
David M. Gustin, Keith A. Rodvold, Jeffery A. Sosman, et al.
Cancer Epidemiol Biomarkers Prev 2004;13:850-860.
Updated version
Cited articles
Citing articles
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cebp.aacrjournals.org/content/13/5/850
This article cites 51 articles, 1 of which you can access for free at:
http://cebp.aacrjournals.org/content/13/5/850.full#ref-list-1
This article has been cited by 4 HighWire-hosted articles. Access the articles at:
http://cebp.aacrjournals.org/content/13/5/850.full#related-urls
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cebp.aacrjournals.org on July 12, 2017. © 2004 American Association for Cancer Research.