Vol 3, Issue 2, 2021 (88-77)
http://journal.unpad.ac.id/idjp
*Corresponding author,
e-mail : tkyaraki@gunma-u.ac.jp (Takuya Araki)
https://doi.org/10.24198/idjp.v3i2.37368
2022 Ishikawa et al
Development of a quantitative method for sunitinib N-oxide using LC-MS/MS
Yuya Ishikawa1,2, Takuya Araki, Ph.D.1,2, Miki Takenaka Sato, Ph.D.1,2,3, Hideaki
Yashima, Ph.D.2, Daisuke Nagano, Ph.D.1, Koujirou Yamamoto, Ph.D.1,2
1Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School
of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan
2Department of Pharmacy, Gunma University Hospital, 3-39-15 Showa-machi, Maebashi,
Gunma 371-8511, Japan
3Division of Pharmacotherapeutics, Department of Clinical Pharmacy, Showa University
School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Submitted : 24 December 2021, Revised : 12 January 2022, Accepted : 13 January 2022
Abstract
We developed a simple method for quantifying sunitinib N-oxide (SNO) in human serum using
a supported liquid extraction (SLE) method and liquid chromatography/tandem mass
spectrometry (LC-MS/MS) to assess the impact of SNO on adverse drug reactions (ADRs)
caused by sunitinib. SNO was extracted using an SLE method and analyzed using an Xevo-
TQ (Waters) LC-MS/MS system. SNO and voriconazole (internal standard; ISTD) were
detected in ESI positive mode, with transitions at 415.4/326.3 for SNO and 350.1/281.1 for
voriconazole. The retention times of SNO and voriconazole were 2.25 and 2.67 min,
respectively, and good calibration curve was obtained from 0.1–5.0 ng/mL for SNO. The
regression equation (weight = 1/x2) describing the calibration curve in human serum was y =
2.81 × 10-9 x2 + 0.000253 x – 0.00202 (R2 = 0.990), where y is the peak area ratio of SNO
against the ISTD and x is the nominal concentration of SNO. The intra- and inter-assay
accuracy varied between -2.4 and 15.6% and all data except the limit of quantification (LOQ)
were within ±10%. The precision varied between 6.7–15.4% and all data except LOQ were
under 15%. The mean recovery ratio of SNO was 90.3 ± 4.9%, and the mean matrix factor was
0.96 ± 0.031. This is the first report of a method to quantify SNO in blood. This method will
help in elucidating the effects of SNO in humans, contribute to the elucidation of the ADRs
expression factors associated with sunitinib, and aid in optimizing treatment with sunitinib.
Keywords: sunitinib N-oxide, metabolite, adverse drug reaction, hand foot skin reaction
Ishikawa et al / Indo J Pharm 3 (2021) 61-70
89
1. Introduction
Sunitinib malate is a multi-target
tyrosine kinase inhibitor (TKI) and is used
as an oral drug for treating renal cell
carcinoma, gastrointestinal stromal tumor,
and pancreatic neuroendocrine tumor [1-4].
Sunitinib strongly inhibits multiple tyrosine
kinases, including VEGFRs 1-3 and PDGF-
Rs α and β, and exhibits high anticancer
efficacy [4]. However, the therapeutic
efficacy of sunitinib varies greatly among
patients, and adverse drug reactions
(ADRs) such as hand foot skin reaction
(HFSR), a characteristic ADR of sunitinib,
force some patients to abandon treatment
despite high clinical efficacy [5, 6]. Studies
of the inter-individual differences of the
clinical efficacies of TKIs include detailed
investigations of the influence of drug
concentration on the clinical efficacy of
sunitinib, with many studies showing
efficacy depending on the drug
concentration [7-9]. In addition, sunitinib is
metabolized by CYP3A4 to N-desethyl
sunitinib, which exhibits tyrosine kinase
inhibitory activities similar to sunitinib.
Thus, the sum of the concentration of
sunitinib and of N-desethyl sunitinib, and
not the concentration of sunitinib alone, is
likely important in predicting the efficacy
of sunitinib [10]. The clinical usefulness of
dosing designs based on the total sunitinib
concentration has been reported in several
papers[7-9].
Although the expression of some ADRs
in individuals, such as decreased platelet
count, has been reported to depend on the
sum of the concentration of sunitinib and of
N-desethyl sunitinib in blood, many ADRs
such as HFSR, bleeding, and hypertension
are reported to not depend on either the
blood sunitinib concentration or the sum of
the concentration of sunitinib and of N-
desethyl sunitinib [9]. The genetic
polymorphism of ABCG2, a transporter
involved in the extracellular excretion of
sunitinib, has been reported to have a
significant effect on the expression of
ADR, and the frequency of ADR
expression in patients with ABCG2
rs2231142 CC is high [11]. However,
ADRs that interfere with the continuation
of treatment occur with a certain frequency
even in patients with wild type ABCG2
[12], demonstrating that the risk and
cause of ADRs remain insufficiently evalu
ated.
The factors causing ADR were recently
studied by analysis of the metabolites of
drugs, and several studies detected the
causative factors [9, 13-15]. For example,
in sorafenib, classified as a TKI as is
sunitinib, the area under the curve of the N-
oxide has been reported to be significantly
higher in a group of patients that required a
reduced dosage due to ADRs [16], and
therefore the N-oxide form is attracting
attention as a candidate causative agent for
ADRs caused by sorafenib.
Previously, we comprehensively
analyzed the metabolites of sunitinib in the
blood of patients taking sunitinib to search
for the factors causing ADRs due to
sunitinib and reported that sunitinib N-
oxide, a photodegradant of sunitinib, was
detected in the blood of patients taking
sunitinib [17]. Since HFSR caused by
sunitinib has been reported to be
diminished by the administration of
antioxidants [18], we considered that
sunitinib N-oxide may affect the expression
of ADRs such as HFSR. However,
currently there is no method for measuring
the blood concentration of sunitinib N-
oxide, and the impact of sunitinib N-oxide
on the expression of ADRs has not been
assessed. So, in this study, we developed a
method for measuring the concentrations of
Ishikawa et al / Indo J Pharm 3 (2021) 61-70
70
sunitinib N-oxide in blood to clarify the
impact of sunitinib N-oxide on the
expression of ADRs of sunitinib.
To date, many methods using liquid
chromatography with ultraviolet detection
(LC-UV) or liquid chromatography-tandem
mass spectrometry (LC-MS/MS) have been
reported as methods for analyzing sunitinib
and N-desethyl sunitinib [19-21]. However,
since the concentration of sunitinib N-oxide
was estimated to be about 1/10 to 1/20 that
of sunitinib in our previous study [17], an
analytical method that is more sensitive
than that used for quantifying sunitinib is
required to study the effect of sunitinib N-
oxide on the body. Therefore, in this study,
we used a supported liquid extraction (SLE)
pretreatment method to concentrate
thesample and analyzed sunitinib and its
metabolites in blood using LC-MS/MS
2. Materials and Methods
2.1 Materials
Sunitinib (>99% purity) was
purchased from LC Laboratories (Woburn,
MA, USA), sunitinib N-oxide (>99%
purity) and N-desethyl sunitinib (96%
purity) were purchased from Toronto
Research Chemicals (Toronto, Canada) and
voriconazole (>98% purity) was purchased
from Tokyo Chemical Industry Co., Ltd.
(Tokyo, Japan). ISOLUTE SLE+ 400 μL
96-well plates (SLE array plates) were
purchased from Biotage Japan Ltd. (Tokyo,
Japan). All other reagents were obtained
from commercial sources and were of
LCMS, HPLC, or special grade.
2.2 Preparation of stock solutions,
working solutions, calibration
samples, and quality control
samples
Primary stock solutions of 1.0 mg/mL
of sunitinib N-oxide, sunitinib, N-desethyl
sunitinib, and voriconazole, used as an
internal standard (ISTD), were separately
prepared in methanol. The primary stock
solution of mixture of sunitinib N-oxide,
sunitinib, and N-desethyl sunitinib was
diluted with 50% methanol to yield
standard working solutions(0.5, 1.25, 2.5,
5, 12.5, 25, 50, 125, 250, 500, and 1250
ng/mL). The primary stock solution of the
ISTD was diluted in 50% methanol to 1
μg/mL or 100 ng/mL. The stock solutions
and other diluted solutions were stored at -
20°C and 4°C, respectively, under dark
conditions. All solutions were equilibrated
to room temperature before use. Calibration
samples and quality control (QC) samples
were prepared by spiking blank pooled
human serum (PHS) with a given volume of
different working solutions. The
concentrations of sunitinib N-oxide for the
calibration sample of sunitinib N-oxide
were set at 0.1, 0.25, 0.5, 1, 2.5, and 5
ng/mL. Calibration samples for sunitinib
and N-desethyl sunitinib were prepared at 7
concentrations: 2.5, 5, 10, 25, 50, 100, and
250 ng/mL. QC samples of sunitinib N-
oxide as the lower limit of quantitation, low
level, middle level, and high level were set
as 0.1, 0.25, 1, and 5 ng/mL, respectively,
and those of sunitinib and N-desethyl
sunitinib were set as 2.5, 5, 50, and 250
ng/mL, respectively.
2.3 Sample preparation
The serum samples for analysis of
sunitinib N-oxide were treated using an
SLE array plate. Briefly, a mixture of 50 μL
of blank PHS, 10 μL of a standard working
solution, 10 μL of the ISTD (100 ng/mL),
and 330 μL of 1% aqueous ammonia was
applied onto an ISOLUTE SLE+ 400 μL
96-well plate (Biotage) sitting on top of a
clean 96-well collection plate. Positive
pressure was applied for 2 s to initiate flow,
Ishikawa et al / Indo J Pharm 3 (2021) 61-70
71
and the sample was allowed to stand for 5
min to absorb into the diatomaceous earth
extraction bed. Ethyl acetate (700 μL) was
added to the SLE array plate to elute the
analytes. This elution process was repeated
two more times.
The samples in the collection plate
were evaporated to dryness under nitrogen
at 40°C. The residue was dissolved in 100
μL of 50% methanol and filtered using a
0.2-μm spin filter. The filtrate was heated at
90°C for 30 min and then cooled at 4°C for
a sufficient time using a thermal cycler. The
solution after heat treatment was used as an
analysis sample, and 10 μL of sample was
used for LC-MS/MS analysis. The sunitinib
and N-desethyl sunitinib samples were
treated using a slightly modified method
from that used for sunitinb N-oxide.
Briefly, the concentration of the ISTD was
1 μg/mL, the residue was dissolved in 250
μL and the sample volume used for LC-
MS/MS analysis was 2 μL.
2.4 Detection of sunitinib and
metabolites
A tandem quadrupole mass
spectrometer was used to detect sunitinib
and its metabolites. A Xevo-TQ (Waters)
with ESI spray in positive ionization mode
was used with the following ionization
parameters: capillary voltage, 2.5 kV;
desolvation temperature, 500°C; source
temperature, 150°C; desolvation gas flow,
950 L/h; and cone gas flow, 50 L/h. The
following transitions were monitored:
415.4/326.3 for sunitinib N-oxide,
399.4/283.2 for sunitinib, 371.4/283.2 for
N-desethyl sunitinib, and 350.1/281.1 for
voriconazole. The sample cone voltage and
collision energy were 22 V and 20 V for
sunitinib N-oxide, 30 V and 30 V for
sunitinib, 22 V and 22 V for N-desethyl
sunitinib, and 20 V and 16 V for
voriconazole, respectively. LC was
performed with an ACQUITY UPLC🄬
system (Waters) equipped with an
ACQUITY UPLC BEH🄬 C18 separation
column (2.1 mm × 50 mm, 1.7 μm)
(Waters). The LC conditions were as
follows: column temperature, 40°C; mobile
phase, 10 mM ammonium formate in
MilliQ water (A) and 0.1% formic acid in
acetonitrile (B); flow rate, 0.3 mL/min; and
gradient program, 20% to 80% B in 3.0
min, 80% to 95% B in 0.1 min, 95% B for
0.2 min, 95% to 20% B in 0.2 min, and 20%
B for 1.5 min.
2.5 Assay validation
Precision was measured as the
coefficient of variation expressed as a
percentage, and accuracy was expressed as
the relative error of the nominal versus the
measured concentration. The intra-assay
variability was tested by measuring three
different PHS samples against the same
calibration curve. The inter-assay
variability was tested on three different
days and a new calibration curve was
constructed for each day. The matrix effect
was also evaluated quantitatively by
measurement of the matrix factor.
The recovery ratio in extraction
process was assessed by comparing quality
control samples in blank PHS
thatunderwent SLE with samples of the
same concentration obtained by simply
diluting the standard working solution.
The matrix factor was calculated by
comparing the peak area of the sample
obtained by spiking the compounds into
SLE-treated blank PHS with that obtained
by spiking the compound into 50%
methanol.
Ishikawa et al / Indo J Pharm 3 (2021) 61-70
72
3. Results
3.1 Detection of sunitinib and its
metabolites
Typical chromatograms of blank PHS
and of blank PHS spiked with sunitinib N-
oxide, sunitinib, N-desethyl sunitinib, and
voriconazole are shown in Figure 1.
The retention times of sunitinib-
Noxide, sunitinib, N-desethyl sunitinib, and
voriconazole were 2.25, 2.26, 2.09, and
2.67 min, respectively. The E-form of
sunitinib and its metabolites, produced by
photodecomposition reactions, were not
detected.
3.2 Validity of the calibration curve,
accuracy and precision
Good calibration curves were obtained
from 0.1 to 5 ng/mL for sunitinib N-oxide
and 2.5–250 ng/mL for sunitinib and N-
desethyl sunitinib. For all three compounds,
the weighting was set as 1/x2 and the
calibration curve was processed by
quadratic curve fitting. The regression
equation describing the calibration curve in
PHS was y = 2.81 × 10-9x2 + 0.000253x +
0.00202 (R2 = 0.990) for sunitinib N-oxide,
y = 9.81 × 10-6x2 + 0.0259x + 0.00107 (R2
= 0.995) for sunitinib, and y = -4.94 × 10-
7x2 + 0.0235x + 0.00107 (R2 = 0.995) for N-
Ishikawa et al / Indo J Pharm 3 (2021) 61-70
73
desethyl sunitinib, where y is the peak area
ratio of the target compound against the
ISTD and x is the nominal concentration of
the target compound.
The results of accuracy and
precision are shown in Tables 1 and 2.
Ishikawa et al / Indo J Pharm 3 (2021) 61-70
74
3.3 Extraction recovery
The recovery of sunitinib N-oxide and
ISTD prior to SLE treatment for the assay
of sunitinib N-oxide and the recovery of
sunitinib, N-desethyl sunitinib and
ISTD prior to SLE treatment for the assay
of sunitinib and N-desethyl sunitinib are
shown in Table 3. All recoveries were
>80%.
3.4 Interference and matrix effect
The relative standard deviation was
less than 15% and peaks corresponding to
sunitinib and its metabolites were not
detected in the blank PHS sample. The
matrix factors are shown in Table 3,
suggesting that no significant matrix effect
was observed and thus had no adverse
impact on the quality of the data.
4. Discussion
Sunitinib N-oxide has been the urine of
animals such as rats, human blood [22].
Therefore, the effects of sunitinib N-oxide
on the human body have not been
investigated well, and to date there is no
analytical method for sunitinib N-oxide in
blood. Previously, we found that sunitinib
N-oxide, a photodegradant of sunitinib, is
found in the blood of patients taking
sunitinib [17], and to clarify the effect of
sunitinib N-oxide on the onset of ADRs
associated with sunitinib, we developed a
simple method for measuring the sunitinib
N-oxide concentration in blood. We
previously reported that the concentration
of sunitinib N-oxide is estimated to be
about 1/20 that of sunitinib [17], so it was
difficult to apply the measurement method
of sunitinib directly to analysis of sunitinib
N-oxide, and therefore a more sensitive
method than previously reported methods
used for sunitinib is needed. Here, we used
sample enrichment as a pretreatment and an
LC-MS/MS method for analyte detection,
and developed a method for measurement
of sunitinib N-oxide with good calibration
curve (R2 ≧ 0.99). This is a first report on
the measurement method of sunitinib N-
oxide.
Sunitinib is light-unstable and converts
from the Z form to the E form upon light
exposure [23]. The blood concentration of
sunitinib (typically Z-sunitinib) may be
underestimated because of generation of
the E form, and the sum of the E and Z form
concentrations is generally evaluated as the
sunitinib concentration [24]. However,
since the ionization efficiency at the time of
elution of the E and Z forms may differ
upon LC separation using a gradient
method, as is typical in analyses using
MS/MS, the sum of the concentrations of
the E and Z forms cannot be evaluated by
simply adding the obtained peak areas. In
addition, there is currently no technique for
maintaining the E and Z forms separately in
a liquid sample, and therefore we cannot
perform accurate absolute quantification
using these standard products. This issue
was addressed by converting the E form to
the Z form by heat-treating the sample
according to the reports by Posocco et al.
[25] and Marangon et al. [26]. Although
details of the conversion efficiency from
the E to the Z form by heating have not been
clarified, at least in the analysis of sunitinib
N-oxide using our method, no E form of
sunitinib N-oxide was detected, and no
sunitinib E form was also detected when
analyzed using our method, which can
detect sunitinib at concentrations 20 times
lower than the lower limit of detection of
methods used in previous reports (data not
shown). In addition, the E form in samples
at the time of LC injection is estimated to
be less than 0.1% of each sunitinib
Ishikawa et al / Indo J Pharm 3 (2021) 61-70
74
concentration used in our study, indicating
that the E form is converted to the Z form
with sufficient efficiency.
A deproteinization pretreatment
method is typically used to analyze
sunitinib using LC-MS/MS. However,
since a sample enrichment is needed to
analyze sunitinib N-oxide as described
above, the SLE method was adopted to
pretreat the samples in this study. The SLE
method has been used to measure many
drugs because of its ease and rapidity but
details of its application to sunitinib and its
metabolites have not been reported.
Ishikawa et al / Indo J Pharm 3 (2021) 61-70
75
Therefore, in this study, we evaluated in
detail the applicability of the SLE method
to the LC-MS/MS analysis of sunitinib and
its metabolites and confirmed the utility of
this approach. SLE method has a higher
capacity to remove proteins from serum and
can accurately recover the target
components. In addition, the solid-phase
extraction method requires washing after
fixation of the target components on the
solid phase, which requires many steps,
while the SLE method does not require
washing, thus shortening the working time
and achieving high recovery ratio. Due to
these characteristics, the pretreatment
method using SLE is not easily affected by
the skills of technicians and can be said to
be one of the methods suitable for clinical
application. Furthermore, SLE likely
increases the purity of the samples injected
onto LC-MS/MS, facilitating the analysis
of a large number of samples.
In addition, we tried to separate the
peaks corresponding to sunitinib and
sunitinib N-oxide by LC but complete
separation was not achieved in the short
time analysis. Although many LC-UV
methods have been reported for measuring
sunitinib and N-desethyl sunitinib
concentrations [19], these compounds
cannot be distinguished by UV, raising the
possibility of overestimating the
concentration of sunitinib by LC-UV
analysis. Therefore, LC-UV is not
amenable to rapid analysis of the
concentrations of sunitinib and its
metabolites and an LC-MS/MS method is
recommended.
In conclusion, we reported the first
report on the method for analyzing the
blood concentration of sunitinib N-oxide, a
sunitinib metabolite in the human body.
Our analysis method for of sunitinib N-
oxide, sunitinib and N-desethyl sunitinib is
simple and the analytes are made more
stable by pretreatment using an SLE
method and heat treating the sample. Since
our method requires only simple steps and
a column, it is not easily affected by
variations in operator skill. We believe that
the method reported here will facilitate
understanding of the effects of sunitinib N-
oxide in humans, contribute to elucidation
of the ADR expression factors associated
with sunitinib, and aid in optimizing
treatment with sunitinib.
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