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.
The sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60 mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC0→∞, 31% and 27% lower liver and kidney AUC0→∞ and 2.2-fold higher AUC0→∞ in brain (all p
Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC0→∞ 38% in plasma (p