The oxidation and hypoglycaemic effect of sorafenib in streptozotocin-induced diabetic rats

BACKGROUND: Diabetes reduces the activity of CYP3A4 and may increase the exposure for the drugs metabolized by the isoenzyme. Sorafenib is a multi-targeted tyrosine kinase inhibitor (TKI), used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. The TKI undergoes CYP3A4-dependent oxidative transformation, which may be influenced by hyperglycaemia. The aim of the study was to compare the oxidation for sorafenib between healthy and streptozotocin-induced diabetic rats. Additionally, the effect of sorafenib on glucose levels was investigated. METHODS: The rats were assigned to the groups: streptozotocin-induced diabetic (DG, n = 8) or healthy (HG, n = 8). The rats received sorafenib orally as a single dose of 100 mg/kg. The plasma concentrations of sorafenib and its metabolite N-oxide were measured with the validated high-performance liquid chromatography with ultraviolet detection. RESULTS: The difference between groups in C(max) and AUC(0−t) values for sorafenib were significant (p = 0.0004, p = 0.0104), and similarly for the metabolite (p = 0.0008, p = 0.0011). Greater exposure for the parent drug and analysed metabolite was achieved in diabetic group. However, the C(max), AUC(0−t), and AUC(0−∞) ratios between the metabolite and sorafenib were similar in both groups. The significant reduction of glycaemia was observed only in the diabetic animals. CONCLUSION: The findings of the study provide evidence that diabetes significantly influence on the exposition for sorafenib and its metabolite, but similar ratios N-oxide/sorafenib for AUC and C(max) in healthy and diabetic animals suggest that oxidation of the TKI is rather unchanged. Additionally, sorafenib-associated hypoglycaemia was confirmed in diabetic animals.