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Sunitinib tissue distribution changes after coadministration with ketoconazole in mice

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Abstract

Sunitinib is a multitargeted tyrosine kinase inhibitor approved for gastrointestinal stromal tumor (GIST), advanced renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors. It is metabolized via CYP3A4 and has low brain penetration due to efflux transporters ABCB1B and ABCG2. We studied the interaction with ketoconazole (50 mg/kg), antifungal drug which shares metabolic pathways and efflux transporters, in ICR female mice after oral coadministration (30 min apart) of 60 mg/kg sunitinib (study group) versus sunitinib alone (control group). Plasma, liver, kidney and brain sunitinib concentrations were measured by HPLC at 2, 5, 10, 20, 40 min, 1, 2, 4, 6, 12 h post-sunitinib administration, and non-compartmental pharmacokinetic parameters estimated. In plasma, ketoconazole coadministration increased plasma maximum concentration (C MAX) 60 %, delayed time to C MAX (T MAX); 1.6-fold greater area under the curve AUC0→∞ (p < 0.001); lower apparent steady-state volume of distribution (V SS/F) and oral clearance (Cl/F) 40 and 61 %, respectively; and shorter elimination half-life (t 1/2). Sunitinib exhibited extensive tissue distribution which increased after ketoconazole coadministration: total area under the curve (AUC0→∞) increased 1.8-, 2.8- and 1.2-fold in kidney, liver and brain, respectively (all p < 0.001). Sunitinib presented high tissue-to-plasma AUC0→∞ ratio in liver (17.8 ± 1.2), kidney (14.6 ± 1.52) and brain (2.25 ± 0.18) which was modified after coadministration: AUC0→∞ ratio increased in liver (31.4 ± 4.7; p < 0.001), kidney (17.1 ± 2.2; p > 0.05) and decreased in brain (1.70 ± 0.23, p > 0.05). The results showed a significant ketoconazole–sunitinib interaction that affected plasma, tissue pharmacokinetics and tissue uptake mechanisms. The study portrays the risk to increase toxicity and potential clinical translatability to treat tumors in tissues.

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Acknowledgments

The authors thank Ms NorBazlin Md Marham and Ms Amy Saik for technical assistance. The authors acknowledge the International Medical University for funding Grant B1/06-Res(08)2009.

Conflict of interest

The authors declare that they have no conflict of interest.

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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, Av. Joan XXIII s/n, Barcelona, 08028, Spain

  2. Adeline Yi Ling Lim

    Present address: Department of Medicine, Alfred Hospital, 55 Commercial Road, Prahran, VIC, 3181, Australia

Authors and Affiliations

  1. Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia

    Evelyn Li-Ching Chee & Ignacio Segarra

  2. Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia

    Adeline Yi Ling Lim

  3. Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, Barcelona, 08028, Spain

    Pilar Modamio & Cecilia Fernandez-Lastra

  4. C/Sant Albert 4, Valldoreix, 08197, Barcelona, Spain

    Ignacio Segarra

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  1. Evelyn Li-Ching Chee
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Correspondence to Ignacio Segarra.

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Chee, E.LC., Lim, A.Y.L., Modamio, P. et al. Sunitinib tissue distribution changes after coadministration with ketoconazole in mice. Eur J Drug Metab Pharmacokinet 41, 309–319 (2016). https://doi.org/10.1007/s13318-015-0264-7

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