Effect of epigallocatechin-3-gallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers
Drug Design, Development and Therapy
effect of epigallocatechin-3-gallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers
Tae-eun Kim 1
Yunjeong Kim 0
Ji-Young Jeon 0
Min-gul Kim 0 2
0 c enter for clinical Pharmacology, Biomedical r esearch institute, c honbuk n ational University hospital , Jeonju, Jeonbuk
1 Department of c linical Pharmacology, Konkuk University Medical center , seoul
2 Department of Pharmacology, c honbuk n ational University Medical school , Jeonju, Jeonbuk, republic of Korea
Previous in vitro studies have demonstrated the inhibitory effect of green tea on drug transporters. Because rosuvastatin, a lipid-lowering drug widely used for the prevention of cardiovascular events, is a substrate for many drug transporters, there is a possibility that there is interaction between green tea and rosuvastatin. The aim of this study was to investigate the effect of green tea on the pharmacokinetics of rosuvastatin in healthy volunteers. An open-label, three-treatment, fixed-sequence study was conducted. On Day 1, 20 mg of rosuvastatin was given to all subjects. After a 3-day washout period, the subjects received 20 mg of rosuvastatin plus 300 mg of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea (Day 4). After a 10-day pretreatment of EGCG up to Day 14, they received rosuvastatin (20 mg) plus EGCG (300 mg) once again (Day 15). Blood samples for the pharmacokinetic assessments were collected up to 8 hours after each dose of rosuvastatin. A total of 13 healthy volunteers were enrolled. Compared with the administration of rosuvastatin alone, the concomitant use at Day 4 significantly reduced the area under the concentration-time curve from time 0 to the last measurable time (AUClast) by 19% (geometric mean ratio 0.81, 90% confidence interval [CI] 0.67-0.97) and the peak plasma concentration (Cmax) by 15% (geometric mean ratio 0.85, 90% CI 0.70-1.04). AUClast or Cmax of rosuvastatin on Day 15 was not significantly different from that on Day 1. This study demonstrated that co-administration of EGCG reduces the systemic exposure of rosuvastatin by 19%, and pretreatment of EGCG can eliminate that effect of co-administration of EGCG. transporter
rosuvastatin; green tea; EGCG; pharmacokinetics; drug interaction; drug
open access to scientific and medical research
O r i g i n a l r e s e a r c h
Green tea (Camellia sinensis) is one of the most popular beverages in Asia and is
gaining popularity worldwide.1 Recently, green tea has attracted considerable attention
because of its health benefits ranging from improvement of metabolic syndrome to
cancer prevention.2–4 Of note, many studies have reported that green tea reduces the
risk of cardiovascular diseases.5–7 Given that many people aware of its health benefits
consume green tea on a regular basis, there is a possibility that the ingredients in
green tea might interact with other drugs on many levels of pharmacokinetics. Green
tea is highly rich in catechins that have been reported to inhibit drug transporters and
thereby interfere with the transport of many drugs across the cell membrane. Catechins
in green tea include epicatechin, epigallocatechin (EGC), epicatechin-3-gallate (ECG)
and epigallocatechin-3-gallate (EGCG),8 of which EGCG is the most abundant
and biologically active. ECG and EGCG can inhibit or promote drug absorption or
elimination by interacting with the intestinal and hepatic
organic anion transport peptides (OATPs) responsible for
drug absorption from the intestinal lumen and removal
from the bloodstream. An in vitro study9 has reported that
ECG and EGCG decrease the uptake of the model substrate
estrone-3-sulfate by OATP1B1, OATP2B1, and OATP1A2
108 and increase its uptake by OATP1B3. Another in vitro study10
l-u2 also reported the inhibitory effects of green tea on transport
-J21 by transporters such as OATP1B1, OATP1B3, organic cation
on transporter (OCT) 1, OCT2, multidrug and toxic compound
.207 extrusion (MATE) 1, MATE2-K, and P-glycoprotein (P-gp).
.469 These studies suggest that green tea catechins ECG and
.357 EGCG can alter the pharmacokinetic profile of a drug that
/yb is transported by one of these transporters.
com Despite in vitro evidence, only a few drugs have been
.sse reported to have significant interaction with green tea in vivo.
rpe Misaka et al11 reported that green tea ingestion greatly
.odw l.y reduces the plasma concentrations of nadolol by inhibiting
/ww no OATP1A2-mediated uptake. Werba et al1 reported that the
:/s se plasma concentrations of simvastatin increase with
h na comitant administration of green tea, mainly via inhibition
from rsoe of intestinal CYP3A4 and P-gp and hepatic OATP1B1.
deda ropF In this study, we investigated the effect of green tea on
lno the pharmacokinetics of rosuvastatin in healthy volunteers
dow by concomitant administration of green tea ingredient EGCG
ryap with or without pretreatment of EGCG. Rosuvastatin is an
ehT HMG-CoA reductase inhibitor used for treating
hyperchonad lesterolemia in patients with cardiovascular disease. In vitro
tne studies demonstrated that rosuvastatin is a substrate for
pom many drug transporters, including OATP1B1, OATP1B3,
lvee OATP2B1, OATP1A2, Na+/taurocholate cotransporting
,nD polypeptide (NTCP), P-gp, breast cancer resistance protein
isge (BCRP), and multidrug resistance-associated protein 2
gD (MRP2).12–15 In enterocytes, rosuvastatin is absorbed from
rD the intestinal lumen via OATP2B1 and OATP1A2 and
pumped out via BCRP, MRP2, and P-gp; in hepatocytes,
rosuvastatin is transported into the cytoplasm via OATP1B1,
OATP1B3, OATP2B1, and NTCP and excreted into bile via
BCRP, P-gp, and MRP2. Because many of these
transporters (ie, OATP1B1, OATP1B3, OATP2B1, OATP1A2, and
P-gp) are reported to be targets of EGC and EGCG, there
is a great possibility that rosuvastatin and these green tea
catechins interact on many levels of the pharmacokinetics of
rosuvastatin. However, detailed information on in vivo
pharmacokinetics of rosuvastatin is lacking in case of concomitant
administration of rosuvastatin and green tea compounds.
We conducted an open-label, three-treatment,
fixedsequence study as follows. Initially, rosuvastatin was given
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alone; after a 3-day washout period, rosuvastatin was
concomitantly given with a single dose of EGCG; finally, EGCG
was given for 10 days as pretreatment, and then rosuvastatin
and EGCG were given concomitantly. In each treatment,
plasma concentrations of rosuvastatin were measured to
determine its systemic exposure. We also stratified our
analysis per genetic polymorphisms of OATP1B1, OATP2B1, and
BCRP, because single-nucleotide variants of these genes
alter the pharmacodynamic or pharmacokinetic properties
Materials and methods
This study included healthy Korean male or female
volunteers aged 20–55 years. Exclusion criteria were any marked
medical or medication history and any abnormal findings on
physical examination, 12-lead electrocardiogram, or clinical
laboratory tests. Subjects were also excluded from the study
if they had taken any agent or food that was reported to
inhibit or induce transporter OATP or BCRP in the
previous 2 weeks.
To determine the effect of green tea extract on the
pharmacokinetics of rosuvastatin, we conducted an open-label,
threetreatment, fixed-sequence study (Figure 1). Clinical trials
were conducted at Chonbuk National University Hospital.
The institutional review boards of Konkuk University
Medical Center (IRB No KUH1280061) and Chonbuk
National University Hospital (IRB No CUH 2015-03-014)
approved the study protocol, and written informed consent
was obtained from all subjects before study enrollment. All
procedures were performed in accordance with the
recommendations of the Declaration of Helsinki. Furthermore, the
study was conducted in compliance with the current Good
Clinical Practices and other applicable laws and regulatory
requirements currently established in South Korea.
All the study subjects received a 20-mg rosuvastatin tablet
with 150 mL of water by oral route on Day 1. After a 3-day
washout period, they received 300 mg of EGCG followed by 20 mg
of rosuvastatin 1 hour later. From Day 5 through 14, subjects
only received 300 mg of EGCG. On Day 15, just like Day 4,
they received 300 mg of EGCG followed by 20 mg of
rosuvastatin 1 hour later. EGCG was administered as two capsules of
Teavigo™, a commercially available, caffeine-free, 94% pure
crystalline EGCG (Healthy Origins, Pittsburgh, PA, USA).20,21
Food or drinks containing caffeine, grapefruit, or alcohol were
not permitted throughout the study. Smoking was also not
allowed during the study period.
Blood samples (8 mL) were collected predose and 0.5, 1,
2, 4, 6, and 8 hours after the administration of
rosuvastatin for pharmacokinetic analysis. Plasma was obtained by
centrifugation at 3,000 rpm for 10 minutes and transferred
into polypropylene tubes containing 0.2 M sodium acetate
(pH 4.0). The plasma samples were stored at -70°C until
they were analyzed. Rooibos™,22 an automated schedule
broadcast software, was used to manage the pharmacokinetic
blood sampling process.
Plasma concentrations of rosuvastatin were determined
by a validated liquid chromatography–tandem mass
spectrometry (LC-MS/MS) method using rosuvastatin-d6 as
an internal standard. Briefly, plasma (90 µL, added 0.2 M
sodium acetate), rosuvastatin-d6 (10 µL at 1 µg/mL in 50%
methanol), and methanol (500 µL) were mixed thoroughly
and centrifuged at 13,200 rpm for 5 minutes. After
evaporating the supernatant, the residue was reconstituted with 100 µL
of 50% methanol, centrifuged at 13,200 rpm for 5 minutes,
and injected into the LC-MS/MS system. The lower limit of
quantification (LLOQ) for rosuvastatin was 0.5 ng/mL with
a linear calibration range of 0.5–100 ng/mL. Each analytical
batch had six quality control (QC) samples of known values,
ie, two QC samples each for low, intermediate, and high
concentrations. The analytical results were accepted only
when more than four out of six QC sample concentrations
were determined within 15% of known values. Intra- and
interday accuracies were 95.5%–104.2%; intra- and interday
precisions varied with ,6.6 CV%.
The peak plasma concentration (Cmax) and time to Cmax
(ie, tmax) were directly obtained from the observed values.
The area under the concentration–time curve (AUC) from
time 0 to the last measurable time (AUClast) was calculated
using the trapezoidal rule. The elimination rate constant (λz)
was determined from the slope of the terminal log-linear
portion of the plasma concentration–time curve. The area
under the concentration–time curve extrapolated to infinity
(AUCinf) was calculated as AUClast + last nonzero plasma
concentration/λz. Clearance corrected for bioavailability
(CL/F) was obtained by dose divided by AUCinf.
Noncompartmental analyses were performed using Phoenix
WinNonlin® version 6 (Certara, Raleigh, NC, USA).
Genotypes were determined by identifying single-nucleotide
polymorphisms (SNPs) in SLCO2B1, SLCO1B1, and ABCG2
encoding for OATP2B1, OATP1B1, and BCRP, respectively.
SNPs were determined using the Pyrosequencing Assay
performed on the AB 7500 Real-Time PCR System (Applied
Biosystems, Foster City, CA, USA), PyroMark Vacuum
Prep Tool (Biotage AB, Uppsala, Sweden), and PyroMark
Q96 ID (Biotage AB). Briefly, genomic DNA was extracted
from 200 µL of whole blood drawn from each volunteer with
an Exgene Blood SV kit (Geneall BioTechnology, Seoul,
Korea). Then, a polymerase chain reaction (PCR) mixture
(total volume, 20 µL) was prepared with 1 µL of 10 pmol
primer (forward and reverse primer, respectively), 10 µL
of premix Taq polymerase, 7.0 µL of DNase-free water,
and 1 µL of genomic DNA. Genotyping assays were
performed to identify the following SNPs: SLCO1B1 521T.C
(rs4149056), ABCG2 421C.A (rs2231142), and SLCO2B1
935G.A (rs12422149). SNP primers were designed by
PyroMark Assay Design 2.0 software (Biotage AB). The assays
were conducted using the following PCR protocol: initial
denaturation at 95°C for 15 minutes; 45 cycles of
denaturation at 95°C for 15 seconds and annealing/extension at 72°C
for 40 seconds; and final extension at 72°C for 10 minutes.
Then, 3 µL of streptavidin sepharose beads (GE Healthcare
Bio-Sciences AB, Uppsala, Sweden) was added to 40 µL of
binding buffer (Biotage AB) and mixed with 20 µL of PCR
product and 20 µL water for 5 minutes at room temperature
using a Microplate Orbital Shaker (Finepcr, Seoul, Korea).
The beads containing the immobilized templates were
captured on the filter probes after the vacuum was applied and
then washed with 70% ethanol for 10 seconds, denaturation
solution (Biotage AB) for 10 seconds, and washing buffer
(Biotage AB) for 10 seconds. The vacuum was then released,
and the beads were released into a PyroMark Q96 Plate
Low (Biotage AB) containing 40 µL of annealing buffer
(Biotage AB) and 0.5 µM of sequencing primer.
Pyrosequencing reactions were performed using the PyroMark Gold
Q96 Reagents (Biotage AB), which contained the enzyme,
substrate, and nucleotides. The assays were performed on the
PyroMark ID (Biotage AB), the sample genotype was
determined using the PyroMark ID 1.0 software (Biotage AB), and
data analyses were performed with Power Marker software
version 3.25 (Statgen, Raleigh, NC, USA).
To compare Cmax, AUClast, and AUCinf of rosuvastatin between
single administration (Day 1) and concomitant administration
with EGCG (Day 4 or Day 15), we performed a mixed-effects
analysis, in which the subject was a random effect and the
treatment was a fixed effect. The analysis was conducted
with the values log transformed, and the geometric mean
ratios and 90% CI were obtained by exponentiating the mean
difference of the log-transformed values between treatments.
To compare Tmax and CL/F of rosuvastatin between single
administration (Day 1) and concomitant administration with
EGCG (Day 4 or Day 15), the Wilcoxon signed rank test
was used. The Mann–Whitney U test was used to compare
the differences in Cmax and AUClast between concomitant
administration of rosuvastatin and EGCG (Day 4 or Day 15)
and single administration of rosuvastatin (Day 1) across
different genotypes (wild-type vs variant genotype). The
Mann-Whitney U test was also used to compare the values
of Cmax and AUClast between genotypes (wild-type vs variant
genotype) in each treatment period. IBM SPSS Statistics™
21 (version 21; Datasolution Inc., Seoul, Korea) was used
for statistical analysis. Data are reported as mean ± standard
deviation unless indicated otherwise. The two-sided level of
statistical significance was set at 0.05.
This study enrolled two male and 11 female volunteers.
All the subjects completed the study. Their ages were
26.8±4.0 years and weights were 56.2±11.7 kg. The baseline
characteristics are presented in Table 1.
Thirteen adverse events were reported in eight out of
13 subjects. The adverse events were five cases of nausea,
three cases of headache, three cases of abdominal pain,
and two cases of diarrhea. All the adverse events were mild in
intensity and resolved without any treatment. Because all the
adverse events occurred from Day 5 through 14, the period
of single administration of EGCG, they were believed to be
related to the dose of EGCG used in this study.
Table 2 summarizes the pharmacokinetic parameters of
rosuvastatin alone and concomitant rosuvastatin–EGCG
administration. A concomitant administration of EGCG
with rosuvastatin, without any pretreatment with EGCG,
significantly reduced the systemic exposure of rosuvastatin.
When rosuvastatin was given alone on Day 1, its plasma
concentration peaked at 4 hours after the dose. The plasma
concentrations of rosuvastatin peaked at 2 hours post dose
after the concomitant administration of EGCG (Day 4). There
was no significant difference in Tmax between rosuvastatin–
EGCG and rosuvastatin alone on Day 4. Compared with
the rosuvastatin-only regimen, the single-dose concomitant
administration of rosuvastatin and EGCG on Day 4
significantly reduced AUClast by 19% (geometric mean ratio 0.81,
90% CI 0.67–0.97) and AUCinf by 20% (geometric mean ratio
0.80, 90% CI 0.66–0.96), although decreases in Cmax were
not statistically significant (geometric mean ratio 0.85, 90%
CI 0.70–1.04) (Figure 2, Table 2).
of 4 hours post dose, similar to the administration of rosuvastatin
alone (Figure 2, Table 2). There was no significant difference
in AUClast, AUCinf, or Cmax of rosuvastatin between rosuvastatin
alone and rosuvastatin–EGCG on Day 15 (for AUClast, geometric
mean ratio 0.89, 90% CI 0.74–1.07; for AUCinf, geometric mean
ratio 0.85, 90% CI 0.71–1.02; and for Cmax, geometric mean ratio
0.92, 90% CI 0.75–1.12). Cmax, AUClast, and AUCinf in individual
subjects are plotted in Figure 3.
Overall, these pharmacokinetic data indicate that a
singleday concomitant use of EGCG and rosuvastatin significantly
reduces the systemic exposure of rosuvastatin and that a
long-term pretreatment with EGCG does not significantly
alter the pharmacokinetics of rosuvastatin concomitantly
given with EGCG.
effect of single-nucleotide variants of
drug transporters on egcg–rosuvastatin
In contrast to the single-dose rosuvastatin–EGCG
adminThe pharmacokinetics of rosuvastatin is influenced by genetic
istration, a 10-day pretreatment of EGCG did not cause any
polymorphisms of molecular channels responsible for its
significant changes in the pharmacokinetics of rosuvastatin.
transcellular transport.16–19 To determine whether genetic
The plasma concentrations of rosuvastatin peaked at the median
variants of BCRP and OATP2B1 modify the pharmacokinetic
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alone (Day 1)
In this study, we investigated the pharmacokinetics of
rosuvastatin with or without concomitant administration of
EGCG. A single-dose, concomitant administration of EGCG
and rosuvastatin led to a significant reduction in the systemic
exposure of rosuvastatin, whereas a prolonged
pretreatment with EGCG did not change the pharmacokinetics of
rosuvastatin. We believe that the reduction in the systemic
exposure of rosuvastatin with a single dose of EGCG mainly
resulted from the inhibition of intestinal uptake transporters
OATP2B1 or OATP1A2, because inhibition of hepatic
transporters (ie, OATP1B1 or OATP2B1) or intestinal P-gp,
an efflux transporter, would have increased the plasma
concentration of rosuvastatin. Regarding the pharmacokinetics
of rosuvastatin after the 10-day treatment with EGCG, a
plausible explanation is that EGCG inhibits both absorption
and elimination of rosuvastatin, leading to no significant
difference in plasma concentrations of rosuvastatin. EGCG
inhibits intestinal OATP1A2 and OATP2B1, which carry
out drug absorption, and hepatic OATP1B1 and OATP2B1,
which move drugs from the bloodstream into the cell.
Low bioavailability of EGCG23 and its accumulation with
multiple-dose administration24 may be responsible for the
difference in the pharmacokinetics of rosuvastatin between
single-dose and pretreatment with EGCG. The plasma
concentrations of EGCG after single-dose administration are
not likely to be high enough to inhibit hepatic uptake; with
deda ropF interaction between EGCG and rosuvastatin, we compared
lno the changes from the single administration of rosuvastatin
dow (Day 1) in AUClast and Cmax of rosuvastatin between
genoryap types of the respective genes. The result is summarized in
heT Table 3. There was no significant difference in the degree of
nad pharmacokinetic changes between the variants of BCRP or
ten OATP2B1. We did not test for OATP1B1 c.521T.C because
pom this variant was found only in one subject.
vee When we compared the AUClast and Cmax of rosuvastatin
,nD between the genotypes of BCRP within each treatment,
variiseg ant genotype (CA or AA) showed significantly higher Cmax
rguDD aconndsAisUtenCtlawst itthhapnrethveiowusilsdt-utdyipees.(16C,1C8I)nothneDcaoym4p,arwishoinchofwthaes
AUClast and Cmax of rosuvastatin between the genotypes of
OATP2B1 within each treatment period, variant genotype
(GA or AA) showed significantly higher Cmax and AUClast
than the wild-type (GG) on Day 1 and Day 4.
Food or beverages have a potential to interact with a variety
of medications and to alter their pharmacokinetic properties.
Given their beneficial effect on cardiovascular health, green
tea and its ingredients are likely to be consumed by patients
with cardiovascular diseases taking multiple medications.
This possibility raises concerns over the interaction between
green tea and cardiovascular drugs.
multiple doses of pretreatment, the plasma concentrations of
EGCG may have risen enough to inhibit hepatic uptake of
rosuvastatin. Previous studies also support this speculation, as
after dosing, may not be sufficient to determine Tmax, given
the fact that Tmax of rosuvastatin is typically between 2 and
4 hours after dosing. Another limitation is that we were only
a prolonged use or multiple doses of green tea increased the
able to recruit 13 volunteers for this study. A future study
plasma concentrations of simvastatin, probably through the
with a larger sample size is needed to confirm our findings
inhibition of hepatic OATP1B1.1 An alternative explanation
and better define the effect of genetic polymorphisms on
is that prolonged use of EGCG may have caused an
upregugreen tea–rosuvastatin interaction. Because genetic
polylation of transporters in enterocytes, resulting in increased
morphisms of BCRP affect its lipid-lowering efficacy and
uptake of rosuvastatin.
pharmacokinetics,17,18 we tried to find out if these
polymorUnlike previous studies on green tea–drug interaction, we
phisms also modify the interaction between rosuvastatin and
used a predetermined dose of a green tea ingredient instead
EGCG. Although the result was not statistically significant,
of green tea itself. The dose of EGCG (300 mg) used in this
a study involving more participants is needed to yield a
study amounts to at least twice as high as EGCG in a cup
of green tea, given that a 3-g bag of green tea steeped in
definitive answer. The significant difference in AUClast and
Cmax across OATP2B1 genotypes also needs to be confirmed
150 mL of hot water three to eight times releases 90–150 mg
using a large sample size.
of EGCG.25 Given that the IC50 value of EGCG on OATP2B1
inhibition was 101 µM (46.30 mg/L)9 and the Cmax after oral
administration of EGCG 200 mg was 73.7±25.3 mg/L,26
a smaller amount of EGCG could have effectively inhibited
OATP2B1. In addition, many participants in this study
reported several adverse events that are believed to be caused
by a high dose of EGCG. Further study is needed to
determine whether a smaller amount of green tea could alter the
pharmacokinetics of rosuvastatin. Meanwhile, pure EGCG
may differ from green tea itself in the extent of inhibition of
transporters. Roth et al9 reported that only gallated forms of
catechins, namely ECG and EGCG, can inhibit OATP1A2,
OATP1B1, and OATP2B1. Therefore, green tea may exert
greater inhibitory effect on drug transporters than does pure
EGCG because green tea contains both ECG and EGCG.
Our study is also unique in that we studied the
pharmacokinetics of rosuvastatin after both single-dose and
prolonged treatment of EGCG, whereas previous studies
only evaluated the effect of green tea after prolonged use.
Although people who are aware of its health benefit tend to
drink green tea on a regular basis rather than occasionally,
we also wanted to find out if occasional intake of green tea
also affects the pharmacokinetics of rosuvastatin.
There are several limitations in our study. Regarding the
pharmacokinetic profiling, we followed plasma
concentrations of rosuvastatin up to 8 hours after administration, which
may have been too short for its known half-life. However,
the geometric mean ratios determined from AUCinf were
comparable to those determined from AUClast, suggesting
that sampling up to 8 hours after dosing was sufficient to
reflect the systemic exposure of rosuvastatin, although it was
not sufficient to completely define the elimination phase.
In addition, our sampling method, ie, at 1, 2, and 4 hours
This work was supported by Konkuk University Medical
Center Research Grant 2014.
The authors report no conflicts of interest in this work.
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