Sunitinib tissue distribution changes after coadministration with ketoconazole in mice

Area of Science:

• Pharmacology
• Drug Interactions
• Oncology

Background:

• Sunitinib is a tyrosine kinase inhibitor used for gastrointestinal stromal tumor (GIST), advanced renal cell carcinoma (RCC), and pancreatic neuroendocrine tumors.
• It undergoes metabolism by CYP3A4 and has limited brain penetration due to efflux transporters ABCB1B and ABCG2.

Purpose of the Study:

• To investigate the pharmacokinetic interaction between ketoconazole and sunitinib in ICR female mice.
• To assess the impact of ketoconazole on sunitinib plasma and tissue concentrations, including brain penetration.

Main Methods:

• Oral coadministration of sunitinib (60 mg/kg) with or without ketoconazole (50 mg/kg) in female ICR mice.
• Plasma, liver, kidney, and brain sunitinib concentrations were measured using HPLC over a 12-hour period.
• Non-compartmental pharmacokinetic parameters were estimated.

Main Results:

• Ketoconazole increased sunitinib's maximum plasma concentration (C MAX) by 60% and the area under the curve (AUC0→∞) by 1.6-fold.
• Tissue distribution of sunitinib increased, with AUC0→∞ rising 1.8-fold in kidneys, 2.8-fold in the liver, and 1.2-fold in the brain.
• The tissue-to-plasma AUC0→∞ ratio for sunitinib increased in the liver and kidney but decreased in the brain after ketoconazole coadministration.

Conclusions:

• Ketoconazole significantly interacts with sunitinib, altering its plasma and tissue pharmacokinetics.
• The interaction affects sunitinib's tissue uptake mechanisms and distribution.
• This interaction highlights potential risks of increased toxicity and implications for clinical use in treating tumors.