Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug-drug interaction in mice

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 AUC0.8, 31% and 27% lower liver and kidney AUC0.8 and 2.2-fold higher AUC0.8 in brain (all p < 0.001) and had lower liver-and kidney-to-plasma AUC0.8 ratios (p < 0.001) than male control mice. Paracetamol decreased 29% plasma AUC0.8 ( p < 0.05) in male mice and remained unchanged in female mice. In male and female mice, it decreased liver (15%, 9%), kidney (15%, 20%) and brain (47%, 50%) AUC0.8 (p < 0.001) respectively owing to 52% brain uptake efficiency reduction in female mice (p < 0.01). Sunitinib displayed sex-divergent pharmacokinetics, tissue distribution and DDI with potential clinical translatability for the treatment of brain tumor and RCC patients.