Evaluation of the inhibitory effect of azoles on pharmacokinetics of lenvatinib in rats both in vivo and in vitro by UPLC‐MS/MS

Background Lenvatinib is a multitargeted tyrosine kinase inhibitor used in the treatment of a variety of solid tumors. This study aims to investigate the potential pharmacokinetic interactions between lenvatinib and various azoles (ketoconazole, voriconazole, isavuconazole and posaconazole) when ora...

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Veröffentlicht in:Thoracic cancer 2023-11, Vol.14 (33), p.3331-3341
Hauptverfasser: Xia, Mengming, Song, Xueyi, Lu, Zebei, Wang, Yu, Zhou, Quan, Geng, Peiwu, Wang, Shuanghu, Zhou, Yunfang, Wu, Qingjun, Han, Aixia
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Sprache:eng
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Zusammenfassung:Background Lenvatinib is a multitargeted tyrosine kinase inhibitor used in the treatment of a variety of solid tumors. This study aims to investigate the potential pharmacokinetic interactions between lenvatinib and various azoles (ketoconazole, voriconazole, isavuconazole and posaconazole) when orally administered to rats. Methods A total of 30 Sprague–Dawley rats were randomly allocated into five groups and administered 20 mg/kg of ketoconazole, voriconazole, isavuconazole and 30 mg/kg of posaconazole and 0.5% CMC‐Na, through gavage for a duration of 7 days prior to the commencement of the experiment. On the final day, the rats were given 10 mg/kg of lenvatinib. The blood concentration of lenvatinib was determined using UPLC‐MS–MS. In vitro lenvatinib were incubated with azoles and rat liver microsomes (RLMs) or human liver microsomes (HLMs). Molecular docking was lastly used to examine the binding strength of the enzymes and ligands with Autodock Vina. Results AUC and Cmax of lenvatinib significantly increased with each of the azoles (p 
ISSN:1759-7706
1759-7714
DOI:10.1111/1759-7714.15125