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

Pharmacol Rep. 2020 Feb;72(1):254-259. doi: 10.1007/s43440-019-00021-0. Epub 2020 Jan 8.


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 Cmax and AUC0-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 Cmax, AUC0-t, and AUC0-∞ 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 Cmax in healthy and diabetic animals suggest that oxidation of the TKI is rather unchanged. Additionally, sorafenib-associated hypoglycaemia was confirmed in diabetic animals.

Keywords: Metabolism; Sorafenib; Sorafenib-associated hypoglycaemia; Streptozotocin-induced diabetes.

MeSH terms

  • Administration, Oral
  • Animals
  • Area Under Curve
  • Blood Glucose / drug effects
  • Chromatography, High Pressure Liquid
  • Diabetes Mellitus, Experimental / drug therapy*
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Oxidation-Reduction
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Wistar
  • Sorafenib / administration & dosage
  • Sorafenib / pharmacokinetics
  • Sorafenib / pharmacology*
  • Streptozocin


  • Blood Glucose
  • Hypoglycemic Agents
  • Protein Kinase Inhibitors
  • Streptozocin
  • Sorafenib