Pharmacology & Pharmacy, 2013, 4, 542-548
http://dx.doi.org/10.4236/pp.2013.47078 Published Online October 2013 (http://www.scirp.org/journal/pp)
Short-Term Drug-Drug Interaction between Sildenafil and
Bosentan under Long-Term Use in Patients with
Pulmonary Arterial Hypertension
Sachiko Miyakawa1*, Keiichi Odagiri1, Naoki Inui1, Akio Hakamata1, Takahiro Goto2,
Shimako Tanaka3, Shinya Uchida3, Noriyuki Namiki3, Hiroshi Watanabe1
1Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan; 2Depart-
ment of Drug Evaluation and Informatics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 3Department
of Pharmacy Practice and Science, School of Pharmaceutical Science, University of Shizuoka, Shizuoka, Japan.
Email: *s_miya@hama-med.ac.jp
Received August 23rd, 2013; revised September 25th, 2013; accepted October 9th, 2013
Copyright © 2013 Sachiko Miyakawa et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Sildenafil and bosentan are often co-administered for pulmonary arterial hypertension (PAH) treatment. The plasma
concentration of sildenafil can be decreased by half if co-administered with bosentan. Many patients take these agents
simultaneously in the morning and the evening. The aim of this study was to examine the pharmacokinetics of sildenafil
which was interfered with bosentan administration to ascertain whether these agents should be given concomitantly or
separately. A two-way crossover study was conducted in 6 PAH patients with combination therapy of sildenafil and
bosentan. Participants underwent the sequence of treatment phases: phase S (sildenafil administered 3 h before bosen-
tan); phase B (bosentan administered 3 h before sildenafil); and phase C (administered concomitantly). Blood samples
were collected on the last day of each phase. There was no significant difference in maximum plasma concentration or
area under the plasma concentration-time curve (AUC0-8) between phase C and phase S (95.5 ± 24.8 vs. 72.9 ± 40.9 (p =
0.07), 209.7 ± 81.8 vs. 180.2 ± 126.4 (p = 0.24), respectively) or between phases C and B (87.8 ± 42.0 vs. 99.6 ± 33.9 (p
= 0.59), 197.2 ± 88.2 vs. 240.7 ± 121.8 (p = 0.19), respectively) (ng/mL, mean ± standard deviation). Large intra- and
inter-individual variability in sildenafil concentration was noted. The timing of administration of sildenafil and bosentan
does not significantly influence the plasma concentration of sildenafil. Physicians do not need to be overly concerned
about the timing of administration of these drugs to maximize the sildenafil concentration.
Keywords: Drug-Drug Interaction; Pulmonary Arterial Hypertension; Sildenafil; Bosentan; Pharmacokinetics
1. Introduction
Pulmonary arterial hypertension (PAH) is a progressive
and proliferative disease of the small pulmonary vascu-
lature. PAH is characterized by vasoconstriction, throm-
bosis in situ, and vascular remodeling [1,2]. PAH leads
to a progressive increase in pulmonary arterial pressure
(PAP) and pulmonary vascular resistance to provoke right
ventricular dysfunction and, ultimately, death. In the
1980s, PAH was thought to be a deadly disease because
the median survival after the diagnosis was 2.8 years [3].
Since 1990, several PAH-specific drugs have been
approved for the indication of this orphan disease and
survival does seem to have improved in the modern era
[4,5]. Currently, various treatments that focus on sym-
ptom relief and improving the prognosis are available:
prostanoids, phosphodiesterase-5 (PDE-5) inhibitors, and
endothelin receptor antagonists [1]. Sildenafil (a selective
inhibitor of cyclic guanosine monophosphate) and bo-
sentan (an antagonist of endothelin-A and -B receptors)
are drugs used in the treatment of PAH. Sildenafil
improves exercise capacity and reduces PAP [6].
Bosentan reduces PAP and improves exercise capacity as
well as functional class in patients with PAH [7,8].
A combination of a PDE-5 inhibitor and endothelin-1
receptor antagonist is standard therapy for advanced
PAH [9]. Sildenafil and bosentan are often co-admini-
stered but crucial drug-drug interactions between these
agents have been reported. Studies have shown the
*Corresponding author.
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Short-Term Drug-Drug Interaction between Sildenafil and Bosentan under
Long-Term Use in Patients with Pulmonary Arterial Hypertension
543
plasma concentration of sildenafil to be decreased by
50% in the area under the plasma concentration-time
curve (AUC) when co-administered chronically with bo-
sentan in PAH patients [10], whereas the efficacy of
sildenafil is dose dependent [11].
Sildenafil and bosentan are recommended to be ad-
ministered at 8-h intervals (i.e., three times daily (TID))
and 12-h intervals (i.e., twice daily (BID)), respectively,
but not a few patients take these drugs simultaneously in
the morning and evening. The difference in these timings
of administration might have an appreciable influence on
drug-drug interactions. We wanted to know if the phar-
macokinetics of sildenafil was interfered with bosentan
administration. In this way, physicians would then know
whether these agents could be given concomitantly or
separately.
2. Methods
This study protocol complied with the Declaration of
Helsinki and was approved by the Research Review
Board of Hamamatsu University School of Medicine
(Hamamatsu, Japan). Written informed consent was pro-
vided by all participants. The study was registered at the
UMIN Clinical Trials Registry (UMIN000002566).
2.1. Study Design
This was a single-center, open-label, randomized, two-
way crossover, drug-drug interaction study conducted
from January 2008 to March 2009. Enrolled participants
were randomly allocated to either treatment pattern 1 or 2.
Pattern 1 began with phase C and phase S followed by
phase C and phase B, while pattern 2 started with phase
C and phase B followed by phase C and phase S (Figure
1). Phase C (concomitant administration) comprised
sildenafil (RevatioTM; Pfizer, Tokyo, Japan; 20 mg; TID)
at 07.00 h, 13.00 h, and 19.00 h, while bosentan
(TracleerTM; Actelion Pharmaceuticals, Tokyo, Japan;
62.5 mg; BID) was administered at 07.00 h and 19.00 h.
Phase S (sildenafil-first) comprised sildenafil (20 mg;
TID) at 07.00 h, 13.00 h, and 19.00 h, and bosentan (62.5
mg; BID) at 10.00 h and 22.00 h. Phase B (bosentan-first)
comprised sildenafil (20 mg; TID) at 10.00 h, 16.00 h,
and 22.00 h, and bosentan (62.5 mg; BID) at 07.00 h and
19.00 h. Participants followed the instruction of drug
administration at home during the treatment phases.
We also undertook a preliminary study of sildenafil
monotherapy for two participants (participant numbers 1
and 2) to confirm chronic drug-drug interactions between
sildenafil and bosentan.
2.2. Inclusion and Exclusion Criteria
Eligible participants were patients with PAH who received
Figure 1. Details of protocol patterns and phases. Phase C
comprises sildenafil (20 mg; TID) at 07.00, 13.00, and 19.00
h, whereas bosentan (62.5 mg; BID) is at 07.00 h and 19.00
h. Sildenafil and bosentan are administered simultaneously
at 07.00 h and 19.00 h. Phase S comprises sildenafil (20 mg;
TID) at 07.00, 13.00, and 19.00 h, whereas bosentan (62.5
mg; BID) is at 10.00 h and 22.00 h. Sildenafil is ad-
ministered 3 h before bosentan administration. Phase B
comprises sildenafil (20 mg; TID) at 10.00, 16.00, and 22.00
h, whereas bosentan (62.5 mg; BID) is at 07.00 h and 19.00
h. Bosentan is administered 3 h before sildenafil adminis-
tration. Sil (blank arrows): sildenafil, Bos (bold arrows):
bosentan.
combination therapy of sildenafil (20 mg; TID) and
bosentan (62.5 mg; BID) for >1 year. The exclusion
criteria were poor health status, apparent adverse effects
of sildenafil or bosentan, and difficulties in receiving
continuous administration of these drugs.
2.3. Pharmacokinetic and Safety Assessments
On the last day of each treatment phase, participants
visited our institution for blood sampling. Study drugs
were administered in the morning to participants in the
fasted state, with breakfast served 2 h thereafter. After
the baseline blood collection, participants were given
sildenafil (20 mg) and/or bosentan (62.5 mg) according
to the protocol of each treatment phase. Blood samples
for the measurement of sildenafil were collected 0.5, 1,
1.5, 2, 3, 4, 6, and 8 h after sildenafil administration. The
schedule of blood sampling is shown in Table 1. On the
day of blood sampling, the second aliquot of sildenafil of
the day was administrated after the last blood sample was
collected (8 h later), which matched the recommended
regimen of drug administration and was fully tolerable to
PAH patients. Participants were confined to the study
center until the final blood sample was collected.
The plasma concentration of sildenafil was determined
by liquid chromatography/mass spectrometry. Briefly,
100 μL of diazepam (1 μg/mL) as an internal standard
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Short-Term Drug-Drug Interaction between Sildenafil and Bosentan under
Long-Term Use in Patients with Pulmonary Arterial Hypertension
544
Table 1. Timetable of blood sampling day.
Phase C
ha Time Blood
sampling Sildenafil Bosentan Meal
0.0
0.5
1.0
1.5
2.0
3.0
4.0
5.0
6.0
8.0
07.00
07.30
08.00
08.30
09.00
10.00
11.00
12.00
13.00
15.00
*
*
*
*
*
*
*
*
*
*
*
Phase S
h Time Blood
sampling Sildenafil Bosentan Meal
0.0
0.5
1.0
1.5
2.0
3.0
4.0
5.0
6.0
8.0
07.00
07.30
08.00
08.30
09.00
10.00
11.00
12.00
13.00
15.00
*
*
*
*
*
*
*
*
*
*
*
Phase B
h Time Blood
sampling Sildenafil Bosentan Meal
--
0.0
0.5
1.0
1.5
2.0
3.0
4.0
6.0
8.0
07.00
10.00
10.30
11.00
11.30
12.00
13.00
14.00
16.00
18.00
*
*
*
*
*
*
*
*
*
*
*
a-hours from sildenafil administration.
was added to the plasma sample (500 μL). Cold ace-
tonitrile (500 μL) was added to the sample and vortex
mixed to enable deproteination. After centrifugation of
3000 rpm for 10 min at 4˚C, the supernatant fluid was
diluted with water (1.5 mL) and applied to an OASIS
HLB extraction cartridge (Waters, Milford, MA, USA).
The cartridge was washed with 5% methanol in water
(1.0 mL) and eluted with acetonitrile (1.0 mL). The
eluate was evaporated under a stream of nitrogen gas at
40˚C. Micromass ZQ Mass Spectrometer (Waters,
Milford, MA, USA) was operated in positive ion mode at
m/z 475. The limit of quantification was 1 ng/mL, and
the intra-assay coefficient of variation was <6.40%.
The pharmacokinetic parameters for sildenafil were
estimated by non-compartmental analyses from the
concentration-time profile in plasma. The terminal
elimination half-life (t1/2) during the log-linear terminal
phase was calculated from the elimination rate constant
determined by linear regression analyses. The AUC0-8
was calculated using the trapezoidal rule for the observed
values and subsequent extrapolation to 8 h. The oral
clearance was calculated as dose/AUC8-. The maximum
plasma concentration (Cmax) and the time of maximum
concentration (Tma x ) were estimated directly from the
observed plasma concentration-time data.
Safety was evaluated by the findings of physical
examination and vital signs (systemic blood pressure and
pulse rate) at each blood sampling. Biochemical and
hematological assessments (blood cell count and serum
levels of creatinine, aspartate aminotransferase, and
alanine aminotransferase) were undertaken at the first
and last visit to our institution.
2.4. Statistical Analyses
Data are the mean ± standard deviation (SD) of the
indicated numbers. A paired t-test was used to assess
differences in the pharmacokinetic parameters of sildena-
fil between phases C and S as well as phase B. A p-value
of <0.05 was considered significant. Computations were
done using GraphPad Prism version 5.0 (GraphPad Soft-
ware, La Jolla, CA, USA).
3. Results
3.1. Participant Characteristics
Six participants with PAH (two men; age, 37 - 66 years)
in World Health Organization (WHO) functional class
II-III were enrolled. Four participants were classified as
having idiopathic PAH and two subjects with associated
PAH. The mean height (±SD) was 158.5 ± 9.9 cm, and
the mean weight (±SD) was 46.4 ± 7.5 kg. Some
participants had complications: interstitial pneumonia (n
= 2), diabetes mellitus (n = 2), scleroderma (n = 1),
systemic lupus erythematosus (n = 1), polymyositis (n =
1), hyperthyroidism (n = 1), osteoporosis (n = 1), and
gout (n = 1). Two participants had no other disease than
PAH.
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Short-Term Drug-Drug Interaction between Sildenafil and Bosentan under
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545
Participants were taking the following co-administered
medications: furosemide (n = 5), spironolactone (n = 4),
beraprost (n = 4), prednisolone (n = 3), rebamipide (n =
3), warfarin (n = 2), alendronate (n = 2), aspirin (n = 1),
roxatidine (n = 1), lansoprazole (n = 1), sarpogrelate (n =
1), allopurinol (n =1 ), tocopherol (n = 1), zolpidem (n =
1), paroxetine (n = 1), and potassium citrate (n = 1). No
changes to these medications were made during the study.
All participants completed the protocol without wor-
sening of clinical assessments (including routine blood
tests).
3.2. Pharmacokinetics
First, we undertook a preliminary study to confirm the
potential drug-drug interaction of bosentan on the
pharmacokinetics of sildenafil. The sildenafil concentra-
tion-time curves of sildenafil monotherapy and concomi-
tant administration of sildenafil and bosentan are shown
in Figure 2. Compared with sildenafil monotherapy, the
plasma concentrations of sildenafil were lower if ad-
ministered concomitantly with bosentan (62.5 mg). This
effect resulted in a decrease in Cmax of 40.8% for
participant 1 and 54.3% for participant 2, and a decrease
in AUC0-8 of 54.0% for participant 1 and 53.8% for
participant 2.
Next, we evaluated the inter- and intra-individual vari-
ability of the sildenafil concentration during concomi-
tant administration with bosentan. The sildenafil con-
centration-time curves for each participant in phase C are
shown in Figure 3. Inter- and intra-individual variations
were considerable. The same dose of sildenafil (20 mg)
resulted in an AUC0-8 of 79.7 - 370.6 h·ng/mL among the
six participants in phase C. The intraindividual difference
was 1.0 - 2.3 times when comparing the two values in
phase C for each participant.
Figure 2. Change in plasma concentration of sildenafil in
participants 1 and 2. Sildenafil monotherapy vs. sildenafil
plus bosentan. Plasma conce ntration-time curve for partici-
pants 1 and 2 in the preliminary study after administration
of sildenafil (20 mg; TID) alone (dotted line) and with
bosentan (62.5 mg; BID) (solid line).
Figure 3. Inter- and intra-individual variability of sildenafil
concentration. Sildenafil concentration-time curves in phase
C for participants 1 - 6. As the participants underwent
phase C twice, both solid line and dotted line show the sil-
denafil concentration of phase C at different time.
Finally, we investigated how the timing of admini-
stration influenced the sildenafil concentration. The sild-
enafil concentration-time curves comparing phase C with
phase S are shown in Figure 4. The pharmaco-kinetics of
sildenafil in phase S was similar to that in phase C. A
significant difference in AUC0-8 or Cmax was not shown
(Figure 5). The sildenafil concentration-time curves
comparing phase C with phase B are shown in Figure 6:
a significant difference in AUC0-8 or Cmax was not shown
(Figure 7). A summary of these pharmaco-kinetic para-
meters is shown in Table 2.
4. Discussion
We investigated the potential interaction between bosen-
tan and sildenafil in relation to the timing of adminis-
tration of these drugs. We revealed that the sildenafil
concentration was not substantially influenced whether
bosentan was administered concomitantly or admini-
stered separately by 3 h. Furthermore, even in the treat-
ment phase C (administered concomitantly) there was a
considerably large intra-individual variability in sild-
enafil concentration.
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Short-Term Drug-Drug Interaction between Sildenafil and Bosentan under
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546
Figure 4. Sildenafil concentration: phase C vs. phase S.
Mean sildenafil concentration-time curves in phase C
(dotted line) and phase S (solid line).
Figure 5. AUC0-8 and Cmax for sildenafil: phase C vs. phase
S. Mean AUC0-8 (left) and mean Cmax (right) in phase C and
phase S.
Figure 6. Sildenafil concentration: phase C vs. phase B.
Mean sildenafil concentration-time curves in phase C
(dotted line) and phase B (solid line).
Figure 7. AUC0-8 and Cmax for sildenafil: phase C vs. phase
B. Mean AUC0-8 (left) and mean Cmax (right) in phase C and
phase B.
Table 2. Pharmacokinetic parameters of sildenafil at each
phase.
Phase C Phase S P value
Cmaxa (ng/mL)
Tmaxb (h)
t1/2c (h)
AUC0-8d (h·ng/mL)
95.5 (24.8)
0.8 (0.4)
2.2 (0.6)
209.7 (81.8)
72.9 (40.9)
1.3 (0.6)
1.9 (0.6)
180.2 (126.4)
0.07
0.14
0.32
0.24
Phase C Phase B P value
Cmaxa (ng/mL)
Tmaxb (h)
t1/2c (h)
AUC0-8d (h·ng/mL)
87.8 (42.0)
1.3 (0.3)
2.6 (1.6)
197.2 (88.2)
99.6 (33.9)
1.1 (0.4)
1.8 (0.4)
240.7 (121.8)
0.59
0.17
0.23
0.19
Each value is expressed by mean (SD) except P value. n = 6. a-maximum
concentration, b-time of maximum concentration, c-t1/2 terminal elimi-
nation half-life, d-area under the plasma concentration-time curve from 0 h
to 8 h after sildenafil administration.
Several clinical studies have shown significant drug-
drug interactions between sildenafil and bosentan. It has
been reported that bosentan (125 mg; BID) decreased the
Cmax of sildenafil by 55.4% and AUCtau by 62.6% in
healthy volunteers [12]. The mechanism of action of this
drug interaction has been rationalized. That is to say, bo-
sentan induces expression of cytochrome P450 3A4
(CYP3A4) in the liver and intestinal wall via activation
of the pregnane X receptor [13], by which sildenafil is
meta- bolized mainly into the less active metabolite
UK-103, 320 [14,15]. In the present study, we confirmed
that the steady-state of bosentan (62.5 mg; BID) also
reduced the Cmax of sildenafil by 40% - 55% and AUC0-8
by 54% (Figure 2). This finding suggests that even a
lower dose of bosentan can cause drug-drug interactions
through CYP3A4 metabolism.
A significant difference in the plasma level of
sildenafil was not found between concomitant adminis-
tration (phase C) and time-separated administration of
bosentan (phase S or phase B) but an interesting de-
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Short-Term Drug-Drug Interaction between Sildenafil and Bosentan under
Long-Term Use in Patients with Pulmonary Arterial Hypertension
547
creasing trend in sildenafil concentration in phase S
(sildenafil-first) rather than phase C was noted (Figure
4). This phenomenon is explicable through a short-term
drug-drug interaction between sildenafil and bosentan
with respect to CYP3A4 metabolism. Given that CYP3A4
activity is already elevated by chronic use of bosentan,
sildenafil administered alone should be metabolized rea-
dily by a larger amount of activated CYP3A4. Bosentan
is not only an inducer but also a substrate of CYP3A4
[15]. Therefore, bosentan administered concomitantly
can be a competitive inhibitor against sildenafil to
CYP3A4. Consequently, more of the sildenafil can esc-
ape from the enzymatic metabolism upon concomitant
administration with bosentan. In addition, in vitro studies
have suggested that bosentan has an inhibitory effect on
CYP3A4. However, the therapeutic dose (125 mg; BID)
yields a maximum free-plasma concentration of 0.08
μmol/L, which is 800-fold lower than the required
plasma level for efficient inhibition [16]. Accordingly,
the inhibitory effect of bosentan against CYP3A4 in the
clinical setting does not have to be considered.
Orally administered sildenafil is rapidly absorbed
(92%) [17]. The detailed mechanism of action of drug
transporters such as human organic anion transporting
polypeptides (OATPs) and the intestinal efflux pump
MDR1 (P-glycoprotein, ABCB1) engaging with sild-
enafil has yet to be defined. With respect to the drug-
drug interaction with bosentan, these transporters will
probably not alter the pharmacokinetics of sildenafil
because 1) the peak plasma concentration of bosentan at
the recommended dose (125 mg; BID) is 50-fold lower
than that required for efficient inhibition of uptake of
OATPs [18] and 2) bosentan is neither a substrate nor an
inhibitor of MDR1 [19]. There are very few studies on
the distribution or excretion of sildenafil, especially those
relevant to drug-drug interactions. Taking into consi-
deration that 80% of the administered oral dose of
sildenafil is excreted as metabolites predominantly in the
feces [20], excretion of sildenafil in urine does not seem
to play an important part in drug-drug interactions.
Large variability in sildenafil concentrations within the
same individual was noted. Extrinsic conditions were
almost identical in the two phase C regimens: drug admi-
nistration, duration of fasting, observed general condi-
tions, and the environment within the institution. There-
fore, this result suggests intrinsic changes affecting the
plasma concentration of sildenafil (e.g., slight changes in
the intestinal mucosal membrane due to local edema).
This large variability could have nullified the subtle
changes in sildenafil concentration, necessitating a great-
er number of participants to detect significant differences
between treatment phases.
The present study had several limitations. First, the
small number of participants must be considered. Not
only the intra-individual differences described above, but
also inter-individual differences in sildenafil concentra-
tions presented substantial barriers. One patient showed a
distinguishingly higher sildenafil concentration than the
other subjects. Second, CYP3A4 activity in vivo could
not be measured directly because CYP3A4 activity is
determined by phenotype. Typically, steady-state con-
centrations of CYP3A4 are identified by the plasma-
concentration ratio of the substrate and its metabolite
formed by the enzyme. This measurement requires fre-
quent blood sampling throughout the day. Therefore, to
identify the rapid change in CYP3A4 activity in vivo is
extremely difficult. Third, the present study was focused
on the plasma concentration of sildenafil only. Further
studies focusing on the plasma concentration of bosentan
are needed to clarify the drug-drug interaction in both
directions.
Hence, if physicians tell patients to take sildenafil
before taking bosentan, a decrease in sildenafil concen-
tration may result. Concomitant or bosentan-first admini-
stration could maintain the plasma level of sildenafil.
In conclusion, differences in the timings of adminis-
tration of sildenafil and bosentan did not influence the
plasma concentration of sildenafil. Physicians do not
need to be overly concerned about the timing of adminis-
tration of these drugs (concomitantly or separately) to
maximize the sildenafil concentration. The short-term
drug-drug interaction between these agents is limited to
large intra-individual variability.
5. Acknowledgements
The authors thank the patients for their participation in
this study.
6. Conflict of Interest
6.1. Funding
Funding: This research received no specific grant from
any funding agency in the public, commercial, or non-
commercial sectors.
6.2. Competing Interests
Hiroshi Watanabe has received research funding from the
Ministry of Health, Labour and Welfare of Japan, Teika,
Takeda, Mochida, Pfizer, Asteras, and Daiichi Sankyo,
and lecture fees from Pfizer, Acterion, Novartis, Daiich
Sankyo, GlaxoSmithKline and Nihon Shinyaku. Uchida
Shinya and Noriyuki Namiki have received research
funding from Astellas, Takeda, Otsuka, Towa, and Kissei
Pharmaceutical Co., Ltd.
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Short-Term Drug-Drug Interaction between Sildenafil and Bosentan under
Long-Term Use in Patients with Pulmonary Arterial Hypertension
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548
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