Purpose: Pharmacokinetic interaction of sunitinib with diclofenac, paracetamol, mefenamic acid and ibuprofen was evaluated due to their P450 mediated metabolism and OATP1B1, OATP1B3, ABCB1, ABCG2 transporters overlapping features.
Methods: Male and female mice were administered 6 sunitinib doses (60 mg/kg) PO every 12 h and 30 min before the last dose were administered vehicle (control groups), 250 mg/kg paracetamol, 30 mg/kg diclofenac, 50 mg/kg mefenamic acid or 30 mg/kg ibuprofen (study groups), euthanized 6 h post last administration and sunitinib plasma, liver, kidney, brain concentrations analyzed.
Results: Ibuprofen halved sunitinib plasma concentration in female mice (p < 0.01) and showed 59 % lower concentration than male mice (p < 0.05). Diclofenac and paracetamol female mice showed 45 and 25 % higher plasma concentrations than male mice which were 27 % lower in mefenamic acid female mice. Paracetamol increased 2.2 (p < 0.05) liver and 1.4-fold (p < 0.05) kidney sunitinib concentrations in male mice that were lower in female mice (p < 0.01, p < 0.001, respectively). Ibuprofen increased 2.9-fold (p < 0.01) liver concentration in male mice that were higher than in female mice (p < 0.001). Female control mice had 35 % higher sunitinib brain concentration than male mice but the concentration decreased 37, 33, 10 and 57 % in the diclofenac, paracetamol, mefenamic acid and ibuprofen (p < 0.001), respectively. Tissue-plasma concentrations correlations were nonsignificant in control, paracetamol, mefenamic acid and ibuprofen groups but was significant in the diclofenac group in male mice (liver, brain) and female mice (liver, kidney).
Conclusions: These results portray gender-based sunitinib pharmacokinetic differences and NSAIDs selective effects on male or female mice, with potential clinical translatability.
Keywords: Diclofenac; Ibuprofen; Mefenamic acid; Paracetamol; Sex-divergent pharmacokinetics; Sunitinib.