The Impact of Sunitinib N-oxide as APhotodegradation Product of Sunitinib
Miki Takenaka
1,2
, Yuta Takahashi
1,3
, Hideaki Yashima
1,2
, Takuya Araki
1,2,*
, Koujirou Yamamoto
1,2
1
Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School of
Medicine, Maebbashi 371-8511, Japan
2
Department of Pharmacy, Gunma University Hospital, Maebashi 371-8511, Japan
3
Center for Medical Education, Gunma University Graduate School of Medicine, Maebashi 371-8511,
Japan
Received : 10 Dec 2018/Revised : 30 Dec 2018/Accepted :2 Jan 2019/Published 21 Jan 2019
ABSTRACT
During treatment with sunitinib, dosage adjustment according to the monitored blood concentration of
sunitinib and SU12662 is considered useful. On the other hand, the appearance of hand-foot skin reaction
(HFSR) cannot be explained by blood sunitinib concentration alone. Although light exposure greatly affects
skin disorders associated with medication use, the photodegradation of sunitinib has not been studied in
detail. Here, we investigated the photodegradation products of sunitinib using LC-MS and examined
cytotoxic activities using an MTT assay. N-desethyl sunitinib and sunitinib N-oxide were identified as
photodegradation products, and their concentrations increased under irradiation in a time-dependent
manner. Although the IC
50
value of N-desethyl sunitinib in the HEK 293 cell line (11.6 µmol/L) was similar
to that of sunitinib (8.6 µmol/L), the IC
50
value of sunitinib N-oxide (121.9 µmol/L) was over 10 times
higher than that of sunitinib. In addition, N-desethyl sunitinib and sunitinib N-oxide were found in blood
obtained from a patient taking sunitinib (24.7 and 2.3 ng/mL, respectively). Because the appearance of
adverse drug reactions associated with sunitinib can be reduced by using α-tocopherol nicotinate, which
has a strong antioxidant effect, we believe that sunitinib N-oxide might strongly promote the development
of HFSR.
Keywords:sunitinib, sunitinib N-oxide, photodegradation product, light
1. Introduction
Sunitinib, a multi-targeted tyrosine kinase
inhibitor, is used as a first-line drug treatment for
metastatic renal cell carcinoma (RCC) and is
considered to be one of the key drugs for treating
RCC [1-3]. The antitumor activity of sunitinib
depends on its concentration in the blood and, in a
meta-analysis of clinical trials of patients taking
sunitinib for metastatic RCC and gastrointestinal
stromal tumor, patients with a high cumulative area
under the concentration-time curve (AUCcum) of
total sunitinib—reflecting the total amount of
sunitinib and SU12662, an active metabolite of
sunitinib—had a significantly longer time to tumor
progression and overall survival [4]. In addition,
some adverse drug reactions (ADRs) such as
anorexia and fatigue were reported to be correlated
with total sunitinib concentration, and the mean
total sunitinib concentration is also reported to be
higher in patients with bleeding events than in those
without them [5]. Thus, during treatment with
sunitinib, dosage adjustment according to the
monitored concentration of sunitinib and SU12662
in blood is considered useful [6-9].
Noda and colleagues [5] have also reported that
some dose-limiting toxicities of sunitinib, such as
hand-foot skin reaction (HFSR), hypertension, and
blood toxicity, developed irrespective of the total
sunitinib concentration. In addition, the frequency
of HFSR is significantly higher in Japanese people,
although there is no significant difference in the
blood concentration of sunitinib between Japanese
and Western populations [3, 10]. Thus, the
appearance of HFSR cannot be explained solely by
a high blood concentration of sunitinib.
*Corresponding author, https://doi.org/10.24198/idjp.v1i1.19908
e-mail : tkyaraki@gunma-u.ac.jp (T. Araki) 2019 Takenaka et al
Vol 1, Issue 1, 2019 (19-25)
http://journal.unpad.ac.id/IdJP
M. Takenakaet al / Indo J Pharm 1 (2019) 19-25
20
Although HFSR due to sunitinib has been
considered to be caused mainly by damage to the
capillary endothelium due to physical pressure and
VEGF inhibition, the precise mechanisms remain
unclear [11]. The causes of skin disorders linked to
the use of various drugs have been studied, and
several factors and mechanisms have been
elucidated. As an example, light-dependent
photosensitivity is reported to be caused by the
interaction of an active substance generated by light
exposure with constituent components in the body
[12]. In addition, skin disorders linked to a new
quinolone antibacterial agent are caused by
photoreactive substances generated by exposure of
a drug or its metabolites in the skin to light [13]. As
mentioned above, light exposure has been
considered too strongly promote the appearance of
skin disorders associated with medications [14].
Sunitinib and SU12662 have been reported to be
converted from the Z form to the E form by
photoinduced isomerization upon exposure to light
in water [15]. On the other hand, because the sum
of the E and Z forms after irradiation of sunitinib
did not coincide with the original drug amount in
that study, it is conceivable that other
photodegradation products are generated.
However, photodegradation products other than the
E/Z conversion have not been well studied.
Accordingly, in this study, we investigated the
photodegradation products of sunitinib in detail and
studied the possibility that ADRs, including HFSR,
are caused by the photodegradation products of
sunitinib.
2. Method
2.1. Materials
Sunitinib and sorafenib were purchased from
LC Laboratories (Woburn, MA). Sunitinib N-oxide
and N-desethyl sunitinib were purchased from
Toronto Research Chemicals (Toronto, Canada).
Cell Proliferation Kit I (MTT) was purchased from
Roche Diagnostics GmbH (Mannheim, Germany).
The human embryonic kidney cell line HEK 293
was purchased from the Japanese Collection of
Research Bioresources (JCRB) Cell Bank (Osaka,
Japan). ISOLUTE SLE+ column and UV lamp
(SYN185UV1) were purchased from Biotage Japan
Ltd. (Tokyo, Japan) and Merck KGaA (Darmstadt,
Germany), respectively. Culture reagents were
purchased from Wako Pure Chemical Industries
(Osaka, Japan). All other reagents were obtained
from commercial sources, and those used for
analysis were graded for high-performance liquid
chromatography, liquid chromatography-mass
spectrometry (LC-MS), or analytical use.
2.2. Sample preparation
Sunitinib, sunitinib N-oxide, N-desethyl
sunitinib, and sorafenib were dissolved in methanol
and diluted to 1.0 mg/mL with methanol as stock
solutions. Samples were stored in light-proof
bottles at −20°C.
2.3 Analysis of the photodegradation products of
sunitinib
Sunitinib stock solution was diluted to 500
ng/mL with 50% methanol and exposed to room or
UV (185 nm) light at room temperature. Samples
were collected 0, 24, 48, and 72 h after the start of
the irradiation and photodegradation products were
detected and quantified using time-of-flight (TOF)
MS. The structures of these products were
determined using quadrupole MS/MS (qMS/MS).
2.4 MTT assay
The HEK 293 cell line was cultured in a
humidified 5% CO
2
incubator at 37°C. The cells
were seeded at 4 × 10
5
cells/well in a 24-well plate
and cultured for 24 h in Dulbecco's Modified
Eagle's medium (DMEM) containing FBS at 37°C,
followed by incubation at 37°C for an additional 24
h in 900 µL/well of serum-free DMEM. Thereafter,
100 μL of sunitinib, sunitinib N-oxide, and N-
desethyl sunitinib at 0.1, 0.25, 1.0, 2.5, 10, 25, 100,
250, 1000, and 2500 μmol/L in 0.1% DMSO or 100
μL of 0.1% DMSO as control were added for 72 h.
Then, 100 μL of MTT solution was added to each
well and the cells were incubated at 37°C for 4 h.
After the addition of 1 mL of DMSO, the samples
were allowed to stand at room temperature for 1 h
and absorbance at 570 nm was measured. Cell
M. Takenakaet al / Indo J Pharm 1 (2019) 19-25
21
viability was calculated by determining the ratio of
the absorbance to that of the control group.
2.5 Clinical analysis
Blood samples (8 mL) were taken from a patient
who received 37.5 mg/day sunitinib with a 2-week
on/1-week off schedule 24 h after the last dose of
sunitinib. The blood was centrifugedat 3,000 rpm
for 5 min to separate the plasma. A mixture of 50
μL of plasma, 10 μL of 50% methanol or standard
solution in 50% methanol, 10 μL of 100 ng/mL
sorafenib in methanol (as internal standard), and
130 μL of Milli-Q® water (Millipore, Temecula,
CA) was applied into an ISOLUTE SLE+ column
(400 μL capacity). The sample was eluted with 2
mL of ethyl acetate, and the eluate was evaporated
to dryness under reduced pressure. The residue was
dissolved in 50 μL of 50% methanol, and 10 μL was
used for LC-qMS/MS analysis. This study was
approved by the Gunma University Ethical Review
Board for Medical Research Involving Human
Subjects; the patient gave written informed consent
prior to participating in the study.
2.6 Mass spectrometric analysis
Exploration of photodegradation products was
performed usingtime-of-flight mass spectrometry
(TOF MS) on an LCT Premier™ XE (Waters,
Milford, MA), with flow injection mode and in LC-
TOF MS mode for quantification of the detected
photodegradation products. MS analysis was
performed using an electrospray ionization (ESI)
source in positive ionization mode (W mode).
Survey scans were acquired in the range of 100 to
1000 m/z. Instrument settings were as follows:
capillary voltage, 3200 V; sample cone voltage, 30
V; desolvation temperature, 350°C; source
temperature, 130°C; cone gas flow, 60 L/h;
desolvation gas flow, 700 L/h; and aperture 1
voltage, 0 V. For quantification of the detected
photodegradation products, LC was performed
with an ACQUITY UPLC® system (Waters). An
ACQUITY UPLC® BEH C18 column (2.1 mm ×
50 mm, 1.7 μm) (Waters) was used as the LC
column. The LC conditions were as follows:
column temperature, 40°C; mobile phase, 0.1%
formic acid in Milli-Q® water (A) and 0.1% formic
acid in acetonitrile (B); flow rate, 0.3 mL/min;
gradient program, 5% to 35% B in 6 min, 35% to
95% B in 1 min, 95% B for 2 min, and 95% to 5%
B in 1 min.
Tandem quadrupole MS was used to determine
the structure of the photodegradation products in
flow injection mode and analyze the concentration
of sunitinib and its degradation products in the
plasma in LC-MS/MS mode. XevoTQ (Waters)
with ESI turbo spray in the positive ionization
mode was used with the following ionization
parameters: capillary voltage, 3000 V; desolvation
temperature, 500°C; source temperature, 150°C;
desolvation gas flow, 1000 L/h; and cone gas flow,
50 L/h. The following transitions were monitored:
399/283 for sunitinib, 371/283 for N-desethyl
sunitinib, 415/326 for sunitinib N-oxide, and
465/252 for sorafenib. Sample cone voltage and
collision energy were 50 V and 22 V for sunitinib,
32 V and 24 V for N-desethyl sunitinib, and 24 V
and 22 V for sunitinib N-oxide, respectively. For
blood sample analysis, LC was performed with an
ACQUITY UPLC® system (Waters). An
ACQUITY UPLC® BEH C18 column (2.1 mm ×
50 mm, 1.7 μm) (Waters) was used as the LC
column. The LC conditions were as follows:
column temperature, 40°C; mobile phase, 0.1%
formic acid in Milli-Q® water (A) and 0.1% formic
acid in acetonitrile (B); flow rate, 0.5 mL/min; and
gradient program, 5% to 35% B in 6 min, 35% to
95% B in 1 min, 95% B for 2 min, and 95% to 5%
B in 1 min.
3. Result
3.1 Analysis of photodegradation products
In TOF MS analysis of sunitinib exposed to UV
light for 72 h, two clear signals were found at m/z
415.213 and 371.189 (Figure 1). In qMS/MS
analysis, signals at m/z 326, 283, and 255 were
found as fragment ions of m/z 415.2.Because the
pattern of these fragment ions coincided with that
obtained from m/z 399.2 of sunitinib, a
photodegradation product found as the m/z 415.2
ion was identified as a sunitinib oxide, which was
generated by oxidation of the nitrogen atom side of
sunitinib, to which two ethyl groups bind (Figure
2).
M. Takenakaet al / Indo J Pharm 1 (2019) 19-25
22
~
415.213
371.189
A
30
~
399.220 (sunitinib)
20
10
0
300 350 400 450 500
m/z
B
399.218 (sunitinib)
30
20
10
0
300 350 400 450 500
m/z
Figure 1.TOF MS spectrum of sunitinib solution before and after UV irradiation. A: before irradiation. B: after
72-h irradiation.
Figure 2.Fragment ion MS spectrum of photodegradation products.
Similarly, clear signals at m/z 326, 283, and 255
were found as fragment ions of m/z 371.2, and a
photodegradation product found as the m/z 371.2
ion was identified as a deethylate of sunitinib that
was generated by deethylation of the tertiary amine
of sunitinib (Figure 2). In addition, in LC-qMS/MS
analysis, the retention times of the peaks of the
photodegradation products m/z 415/326 and
371/283 were consistent with the retention times of
sunitinib N-oxide (m/z 415/326) and N-desethyl
sunitinib (m/z 371/283), respectively. Furthermore,
the MS spectra of the fragment ions of m/z 415.2
Relative intensity to
sunitinib (%)
M. Takenakaet al / Indo J Pharm 1 (2019) 19-25
23
and 371.2 in UV-irradiated samples were consistent
with the fragment ion MS spectra of m/z 415.2 of
sunitinib N-oxide and of m/z 371.2 of N-desethyl
sunitinib (data not shown).
The concentration of sunitinib decreased in a
time-dependent manner up to 48 h in the UV-
irradiated sample and rapidly decreased after 72 h
(Figure 3A). By contrast, sunitinib was only
slightly decreased after irradiation with indoor
light. Sunitinib N-oxide comprised 64.0% and
77.0% of the photodegradation products in the
100
50
0
-1 0 1 2
Log
10
Concentration of drugs
(μmol/L)
samples exposed to UV light for 48 and 72 h,
respectively (Figure 3B).
A
Figure 4. Cytotoxic activity of sunitinib, N-desethyl
sunitinib, and sunitinib N-oxide. Closed circle, sunitinib;
closed square, N-desethyl sunitinib; open circle, sunitinib N-
oxide.
1,000
750
500
250
0
1,000
750
500
250
0
3.3 Blood concentrations of the photodegradation
products of sunitinib
The concentrations of sunitinib, N-desethyl
0hr 24hr 48hr 72hr 0hr 24hr 48hr 72hr
sunitinib, and sunitinib N-oxide in blood obtained
B
160
120
Under indoor light Under UV light
160
120
from a patient taking sunitinib at trough were 79.9,
24.7, and 2.3 ng/mL, respectively (Figure 5).
A B
(
×
1000)
(
×
1000)
80
40
0
0hr 24hr 48hr 72hr
80
40
0
0hr 24hr 48hr 72hr
1000
750
500
250
m/z 399/283
(E)
(Z)
600
400
200
m/z 371/283
(E)
(Z)
Under indoor light Under UV light
Figure 3. Amount of photodegradation products and duration
0
0 2 4 6 8 10
Time (min)
C D
0
0 2 4 6 8 10
Time (min)
of light exposure. A: Change in the amount of sunitinib and
(
×
1000)
(
×
1000)
the total photodegradation products detected. Closed,
sunitinib (E); open, sunitinib (Z); hatched, degradation
products. B: Change in the amount of each of the
photodegradation products detected. Closed, N-desethyl
sunitinib (E); open, N-desethyl sunitinib (Z); hatched,
sunitinib N-oxide (E); dotted, sunitinib N-oxide (Z).
150
100
50
0
0 2 4 6 8 10
Time (min)
800
600
400
200
0
m/z 465/252
0 2 4 6 8 10
Time (min)
3.2 Analysis of the cytotoxicity of the
photodegradation products of sunitinib
The cytotoxicity of sunitinib and its
photodegradation products N-desethyl sunitinib
and sunitinib N-oxide was assessed by MTT assay.
In contrast to N-desethyl sunitinib (IC
50
value, 11.6
µmol/L), the IC
50
value of sunitinib N-oxide was
over 10 times higher than that of sunitinib in the
HEK 293 cell line (121.9 and 8.6 µmol/L for
sunitinib N-oxide and sunitinib, respectively)
(Figure 4).
Figure 5.Chromatogram of a clinical sample. A: m/z 399/283
(sunitinib); B: m/z 371/283 (N-desethyl sunitinib); C: m/z
415/326 (sunitinib N-oxide); D: m/z 465/252 (sorafenib as
internal standard).
4. Discussion
The risk of developing HFSR, one of the dose-
limiting toxicities of sunitinib, has not been
correlated with the blood concentration of
sunitinib, and so elucidation of the factors leading
to the onset of HFSR is required. We focused on the
skin reactions accompanying light irradiation,
considered an important clinical problem for many
m/z 415/326
(Z)
(E)
Peak area
Peak area
Peak area
Peak area
Intensity (CPS)
Intensity (CPS)
Cell
Viability
(%)
Intensity (CPS)
Intensity (CPS)
M. Takenakaet al / Indo J Pharm 1 (2019) 19-25
24
medicines, and investigated the photodegradation
products of sunitinib. We found for the first time
that sunitinib N-oxide is generated by UV
irradiation of sunitinib and that it is also present in
the blood of a patient taking sunitinib. Although
sunitinib N-oxide was found in plasma and urine as
a micro-decomposition product in an in vivo rat
study, its contribution to drug efficacy and adverse
and pharmacological effects has not been studied
[16].
Recently, α-tocopherol nicotinate was reported
to reduce the appearance of ADRs related to
sunitinib [17]. The authors found that ADR was
reduced due to the hydrogen peroxide trapping
efficacy of α-tocopherol nicotinate. However,
because α-tocopherol nicotinate has a strong
antioxidant effect, we believed that the ADRs of
sunitinib could be suppressed via an antioxidant-
mediated decrease in sunitinib N-oxide generation.
Because we have not assessed the impact of
sunitinib N-oxide on the appearance of HFSR, we
need to fully explore the influence of sunitinib N-
oxide in the human body and the relationship
between sunitinib N-oxide level and HFSR onset in
future research.
In an MTT assay, the cytotoxic activity of
sunitinib N-oxide was found to be lower than that
of sunitinib and N-desethyl sunitinib. These data
suggested that the effect of sunitinib N-oxide on
humans may be different from that of sunitinib and
N-desethyl sunitinib. However, we could not rule
out the possibility that the differences in
intracellular uptake of each substance may have
affected the MTT assay results, and we also did not
evaluate the pharmacological effects of sunitinib N-
oxide in detail. At least for this point, the effect on
sunitinib N-oxide on ADRs remains to be clarified
and requires further in-depth study.
In the analysis of sunitinib and sunitinib-related
compounds using LC, the retention time of
sunitinib N-oxide was very similar to that of
sunitinib. Because they both have the same basic
structure, it may be difficult to distinguish these
compounds by UV detection and accurate long-
term separation analysis is needed to separately
quantify these compounds using a UV detector
[18]. Because the activity of sunitinib and sunitinib
N-oxide was indicated to be different in our study,
we believe that LC-MS/MS but not LC-UV/Vis is
suitable for the separate routine clinical analysis of
sunitinib and sunitinib-related compounds.
5. Conclusion
We found that sunitinib N-oxide was generated
by UV irradiation of sunitinib and could be detected
in the blood of a patient taking sunitinib. Although
the pharmacological effects of sunitinib were not
clarified, we believe that sunitinib N-oxide might
strongly affect the appearance of ADRs because it
has been reported that the ADRs induced by
sunitinib can be ameliorated by antioxidant
treatment. We aim to study the distribution and
pharmacological effects of sunitinib N-oxide and
assess its influence on the development of ADRs of
sunitinib.
Acknowledgements
This study was supported by a grant-in-aid for
scientific research KAKENHI 15H00520 from the
Japan Society for the Promotion of Science.
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