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.
Highlights
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 [1,2,3,4]
Since hand foot skin reaction (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 adverse drug reactions (ADRs) such as HFSR
Sunitinib N-oxide has been detected in the urine of animals such as rats, but not in human blood [22]
Summary
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 [1,2,3,4]. Sunitinib strongly inhibits multiple tyrosine kinases, including VEGFRs 1-3 and PDGFRs α and β, and exhibits high anticancer efficacy [4]. 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 [7,8,9]. Sunitinib is metabolized by CYP3A4 to N-desethyl sunitinib, which exhibits tyrosine kinase inhibitory activities similar to sunitinib. The clinical usefulness of dosing designs based on the total sunitinib concentration has been reported in several papers[7,8,9]
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