The Impact of Sunitinib N-oxide as a Photodegradation Product of Sunitinib

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 IC50 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 IC50 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.Keyword : sunitinib, sunitinib N-oxide, photodegradation product, light

Nitrosonifedipine, a Photodegradation Product of Nifedipine, Suppresses Pharmacologically Induced Aortic Aneurysm Formation

Background/Aims: We have reported that nitrosonifedipine (NO-NIF), a photodegradation product of nifedipine, has strong antioxidant and endothelial protective effects, and can suppress several cardiovascular diseases in animal models. The objective of the present study was to investigate the effects of NO-NIF on aortic aneurysm formation. Methods: The mice were infused with β-aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. The oxidative stress was measured by dihydroethidium staining and nitrotyrosine staining. The expressions of inflammation-related genes were assessed by quantitative real-time PCR and immunohistochemical staining. To clarify the mechanisms of how NO-NIF suppresses vascular cell adhesion molecule (VCAM)-1, endothelial cells were used in in vitro system. Results: NO-NIF suppressed pharmacologically induced the aortic aneurysm formation and aortic expansion without blood pressure changes. NO-NIF suppressed elastin degradation and matrix metalloproteinase-2 mRNA expression. NO-NIF suppressed the reactive oxygen species-cyclophilin A positive feedback loop. Upregulated mRNA expressions of inflammation-related genes and endothelial VCAM-1 were suppressed by NO-NIF co-treatment in aortae. Conclusion: NO-NIF has the potential to be a new, nifedipine-derived therapeutic drug for suppressing aortic aneurysm formation by directly improving aortic structure with its strong ability to reduce oxidative stress and inflammation.