Effects of three flavonoids on the metabolism of lenvatinib

• Published in: Frontiers in pharmacology 2024-08, Vol.15, p.1438259
• Main Authors: Yang, Jinzhao, Chen, Jie, Li, Qingqing, Xu, Ren-Ai, Chen, Xiaohai
• Format: Article
• Language: English
• Subjects: DDIs; flavonoids; hepatocellular carcinoma; lenvatinib; luteolin; Pharmacology
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2024.1438259

Lenvatinib is a first-line therapy for the treatment of hepatocellular carcinoma (HCC), an active multi-target tyrosine kinase inhibitor (TKI). The interaction between Traditional Chinese Medicine (TCM) and chemicals has increasingly become a research hotspot. The objective of this study was to pinpoint the effects of three flavonoids on the metabolism of lenvatinib. Enzyme reaction system was established and optimized , and experiments were conducted in Sprague-Dawley (SD) rats, where the analytes were detected by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). We found that among three flavonoids, luteolin and myricetin had strong inhibitory effects on lenvatinib metabolism, with half-maximal inhibitory concentration (IC ) values of 11.36 ± 0.46 µM and 11.21 ± 0.81 µM in rat liver microsomes (RLM), respectively, and 6.89 ± 0.43 µM and 12.32 ± 1.21 µM in human liver microsomes (HLM), respectively. In Sprague-Dawley rats, the combined administration of lenvatinib and luteolin obviously expanded the exposure to lenvatinib; however, co-administered with myricetin did not have any changes, which may be due to the poor bioavailability of myricetin . Furthermore, the inhibitory type of luteolin on lenvatinib showed an un-competitive in RLM and a mixed in HLM. Collectively, flavonoids with liver protection, especially luteolin, may inhibit lenvatinib metabolism and .