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01-04-2017 | PRECLINICAL STUDIES

Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug-drug interaction in mice

Authors: Ming Hui Liew, Salby Ng, Chii Chii Chew, Teng Wai Koo, Yun Lee Chee, Evelyn Li-Ching Chee, Pilar Modamio, Cecilia Fernández, Eduardo L. Mariño, Ignacio Segarra

Published in: Investigational New Drugs | Issue 2/2017

Summary

The sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60 mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC_0→∞, 31% and 27% lower liver and kidney AUC_0→∞ and 2.2-fold higher AUC_0→∞ in brain (all p < 0.001) and had lower liver- and kidney-to-plasma AUC_0→∞ ratios (p < 0.001) than male control mice. Paracetamol decreased 29% plasma AUC_0→∞ (p < 0.05) in male mice and remained unchanged in female mice. In male and female mice, it decreased liver (15%, 9%), kidney (15%, 20%) and brain (47%, 50%) AUC_0→∞ (p < 0.001) respectively owing to 52% brain uptake efficiency reduction in female mice (p < 0.01). Sunitinib displayed sex-divergent pharmacokinetics, tissue distribution and DDI with potential clinical translatability for the treatment of brain tumor and RCC patients.

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Title: Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug-drug interaction in mice
Authors: Ming Hui Liew
Salby Ng
Chii Chii Chew
Teng Wai Koo
Yun Lee Chee
Evelyn Li-Ching Chee
Pilar Modamio
Cecilia Fernández
Eduardo L. Mariño
Ignacio Segarra
Publication date: 01-04-2017
Publisher: Springer US
Published in: Investigational New Drugs / Issue 2/2017
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-016-0415-y

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