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Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice

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Summary

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 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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Acknowledgements

The authors would like to thank Ms. A. Saik and Ms. N. Marham for their technical assistance.

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  1. Ignacio Segarra

    Present address: Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain

Authors and Affiliations

  1. Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, Kuala Lumpur, Malaysia

    Chii Chii Chew, Salby Ng, Yun Lee Chee, Teng Wai Koo, Ming Hui Liew, Evelyn Li-Ching Chee & Ignacio Segarra

  2. Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain

    Pilar Modamio, Cecilia Fernández & Eduardo L. Mariño

  3. cC/ Sant Albert 4, 08197, Valldoreix, Barcelona, Spain

    Ignacio Segarra

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This research was funded by the International Medical University with grant B1/06-Res(08)2009.

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Chew, C.C., Ng, S., Chee, Y.L. et al. Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice. Invest New Drugs 35, 399–411 (2017). https://doi.org/10.1007/s10637-017-0447-y

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