Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug-drug interaction in mice
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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 < 0.001) and had lower liver- and kidney-to-plasma AUC0→∞ ratios (p < 0.001) than male control mice. Paracetamol decreased 29% plasma AUC0→∞ (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→∞ (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.
KeywordsSunitinib Paracetamol Sex-divergent pharmacokinetics Drug-drug interaction Blood-brain barrier Brain tumor
The authors thank Ms. A. Saik and Ms. N. Marham for their assistance.
Compliance with ethical standards
Conflict of interest
Author MHL declares that she has no conflict of interest. Author SN declares that she has no conflict of interest. Author CCC declares that she has no conflict of interest. Author TWK declares that she has no conflict of interest. Author YLC declares that she has no conflict of interest. Author ELCC declares that she has no conflict of interest. Author PM declares that she has no conflict of interest. Author CF declares that she has no conflict of interest. Author ELM declares that he has no conflict of interest. Author IS declares that he has no conflict of interest.
The work was supported by the International Medical University (IMU), Kuala Lumpur, Malaysia with grant B1/06-Res (08)2009.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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