ABSTRACT
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 AUC0â∞ 38% in plasma (p < 0.05) and 24% in liver (p < 0.001) and 23% in kidney (p < 0.001). However, AUC0â∞ remained unchanged in plasma and increased 41% in kidney (p < 0.001) of female mice. In brain, sunitinib exposure decreased 46% (p < 0.001) and 32% (p < 0.001) in male and female brain respectively. Mechanistically, diclofenac increased the liver uptake efficiency in male (27%, p < 0.05) and female (48%, p < 0.001) mice and 30% in kidney (p < 0.05) of male mice, probably owing to effects on efflux transporters. Sunitinib displayed sex-divergent DDI with diclofenac with probable clinical translatability due to potential different effects in male and female patients requiring careful selection of the NSAID and advanced TDM to implement a personalized treatment.
Subject(s)
Angiogenesis Inhibitors/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Diclofenac/pharmacology , Indoles/pharmacokinetics , Protein Kinase Inhibitors/pharmacokinetics , Pyrroles/pharmacokinetics , Angiogenesis Inhibitors/blood , Animals , Area Under Curve , Brain/metabolism , Drug Interactions , Female , Indoles/blood , Kidney/metabolism , Liver/metabolism , Male , Mice, Inbred ICR , Protein Kinase Inhibitors/blood , Pyrroles/blood , Sex Characteristics , Sunitinib , Tissue DistributionABSTRACT
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 AUC0â∞, 31% and 27% lower liver and kidney AUC0â∞ and 2.2-fold higher AUC0â∞ in brain (all p < 0.001) and had lower liver- and kidney-to-plasma AUC0â∞ ratios (p < 0.001) than male control mice. Paracetamol decreased 29% plasma AUC0â∞ (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%) AUC0â∞ (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.