Vehicle development, pharmacokinetics and toxicity of the anti-invasive agent 4-fluoro-3',4',5'-trimethoxychalcone in rodents

PloS One
Liselot M MusBart I Roman

Abstract

Effective inhibitors of invasion and metastasis represent a serious unmet clinical need. We have recently identified 4-fluoro-3',4',5'-trimethoxychalcone or C16 as a potent anti-invasive molecule. In this paper, we report on the development of an optimized vehicle for oral administration of C16. We also explore its pharmacokinetic and toxicity profile in rodents as a prelude to a broad-scope evaluation as a pharmacological tool in animal models of disease. C16 showed suboptimal pharmacokinetics with limited oral bioavailability and whole blood stability. Rapid metabolism with elimination via glutathione conjugation was observed. An oral dosing routine using medicated gels was developed to overcome bioavailability issues and yielded sustained whole blood levels above the half maximal effective concentration (EC50) in a 7-day study. The compound proved well-tolerated in acute and chronic experiments at 300 mg/kg PO dosing. The medicated gel formulation is highly suitable for evaluation of C16 in animal models of disease.

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Citations

Jan 25, 2020·Molecular Medicine Reports·Xiaokai Duan, Guijun Qin
Mar 1, 2021·Journal of Periodontal Research·Natalie Aparecida Rodrigues FernandesMorgana Rodrigues Guimarães-Stabili
Jun 3, 2021·Cancers·Radka MichalkovaJan Mojzis

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Methods Mentioned

BETA
chip
nuclear magnetic resonance

Software Mentioned

WinNonlin

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