Sunitinib tissue distribution changes after coadministration with ketoconazole in mice

Sunitinib is a multitargeted tyrosine kinase inhibitor approved for gastrointestinal stromal tumor (GIST), advanced renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors. It is metabolized via CYP3A4 and has low brain penetration due to efflux transporters ABCB1B and ABCG2. We studied the interaction with ketoconazole (50 mg/kg), antifungal drug which shares metabolic pathways and efflux transporters, in ICR female mice after oral coadministration (30 min apart) of 60 mg/kg sunitinib (study group) versus sunitinib alone (control group). Plasma, liver, kidney and brain sunitinib concentrations were measured by HPLC at 2, 5, 10, 20, 40 min, 1, 2, 4, 6, 12 h post-sunitinib administration, and non-compartmental pharmacokinetic parameters estimated. In plasma, ketoconazole coadministration increased plasma maximum concentration (C MAX) 60 %, delayed time to C MAX (T MAX); 1.6-fold greater area under the curve AUC0→∞ (p  0.05) and decreased in brain (1.70 ± 0.23, p > 0.05). The results showed a significant ketoconazole-sunitinib interaction that affected plasma, tissue pharmacokinetics and tissue uptake mechanisms. The study portrays the risk to increase toxicity and potential clinical translatability to treat tumors in tissues.