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European Journal of Drug Metabolism and Pharmacokinetics

Published in:

01-06-2016 | Original Paper

Sunitinib tissue distribution changes after coadministration with ketoconazole in mice

Authors: Evelyn Li-Ching Chee, Adeline Yi Ling Lim, Pilar Modamio, Cecilia Fernandez-Lastra, Ignacio Segarra

Published in: European Journal of Drug Metabolism and Pharmacokinetics | Issue 3/2016

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 AUC_0→∞ (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 (AUC_0→∞) 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 AUC_0→∞ ratio in liver (17.8 ± 1.2), kidney (14.6 ± 1.52) and brain (2.25 ± 0.18) which was modified after coadministration: AUC_0→∞ 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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Title: Sunitinib tissue distribution changes after coadministration with ketoconazole in mice
Authors: Evelyn Li-Ching Chee
Adeline Yi Ling Lim
Pilar Modamio
Cecilia Fernandez-Lastra
Ignacio Segarra
Publication date: 01-06-2016
Publisher: Springer International Publishing
Published in: European Journal of Drug Metabolism and Pharmacokinetics / Issue 3/2016
Print ISSN: 0378-7966
Electronic ISSN: 2107-0180
DOI: https://doi.org/10.1007/s13318-015-0264-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Sunitinib tissue distribution changes after coadministration with ketoconazole in mice

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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