Inhibitory effect of resveratrol on famitinib metabolism <i>in vitro</i> and <i>in vivo</i>

Famitinib is a tyrosine kinase inhibitor (TKI) that inhibits angiogenesis, thereby exerting anti-tumor effects. This study was the first to examine the potential impact of 52 traditional Chinese medicines and 75 additional pharmaceutical agents on famitinib metabolism. Furthermore, we sought to elucidate the inhibitory effect of resveratrol on the metabolism of famitinib and its inhibitory mechanism. In vitro findings revealed that 5 traditional Chinese medicines and 14 additional pharmaceutical agents inhibited famitinib metabolism by more than 80%. In vitro studies of resveratrol’s inhibitory effect on famitinib metabolism disclosed that the half-maximal inhibitory concentrations (IC50) were 11.83 and 8.05 μM in rat liver microsomes (RLM) and human liver microsomes (HLM), respectively. The inhibitory mechanisms in RLM and HLM were un-competitive and mixed inhibition, respectively. Co-administration of resveratrol and famitinib led to increases in AUC(0-t), AUC(0-∞), MRT(0-t), MRT (0-∞), t1/2, Cmax, and Tmax of famitinib by 1.03-, 1.21-, 0.48-, 0.91-, 0.96-, 0.62-, and 2.15-fold, respectively, while CLz/F was decreased by 56.4%. Moreover, MRT(0-t), MRT(0-∞), Tmax of the metabolite N-desethylfaminitib (SHR116637) were significantly increased 0.35-, 0.81-, and 1.86-fold, respectively. In vivo and in vitro results indicated that resveratrol inhibited the metabolism of famitinib. When famitinib is used concomitantly with resveratrol, clinicians must closely monitor the concentrations and adverse effects of famitinib and adjust the dosage as needed.