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Sunitinib DDI with paracetamol, diclofenac, mefenamic acid and ibuprofen shows sex-divergent effects on the tissue uptake and distribution pattern of sunitinib in mice

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Abstract

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.

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Acknowledgments

The authors thank the International Medical University for financial support: B1/07-Res(09)2010.

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Author notes

  1. Ignacio Segarra

    Present address: Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain

Authors and Affiliations

  1. Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

    Siok Yean Tan, Mei Mei Wong, Angela Lu Wun Tiew, Yai Wen Choo, Suat Hun Lim & Ignacio Segarra

  2. Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

    Ing Hong Ooi

  3. Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain

    Pilar Modamio, Cecilia Fernández & Eduardo L. Mariño

  4. University of Barcelona, Avn Joan XXIII s/n, 08028, Barcelona, Spain

    Ignacio Segarra

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Tan, S.Y., Wong, M.M., Tiew, A.L.W. et al. Sunitinib DDI with paracetamol, diclofenac, mefenamic acid and ibuprofen shows sex-divergent effects on the tissue uptake and distribution pattern of sunitinib in mice. Cancer Chemother Pharmacol 78, 709–718 (2016). https://doi.org/10.1007/s00280-016-3120-9

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