Abstract
Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60mg/kg PO sunitinib alone (control groups) or with 30mg/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<0.05) and 24% in liver (p<0.001) and 23% in kidney (p<0.001). However, AUC0→∞ 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.
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