Effect of apatinib on albendazole metabolism in vitro and in vivo

Albendazole is a broad-spectrum antiparasitic benzimidazole and has potential for the treatment of tumors. The aim of this study was to investigate the potential inhibitory effects of 77 drugs on the metabolism of albendazole, and further to elaborate the inhibitory mechanism of apatinib on albendazole metabolism in vitro and in vivo, where the concentrations of albendazole and its metabolites were detected using an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay. In vitro results showed that 10 drugs inhibited albendazole metabolism by more than 80%, with the half-maximal inhibitory concentrations (IC₅₀) of apatinib in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 (rCYP3A4) being 0.47, 5.53 and 2.01 μM, respectively. Moreover, the inhibition of albendazole by apatinib was non-time-dependent. In addition, the inhibitory mechanisms were mixed consisting of non-competitive and un-competitive for RLM, and competitive and non-competitive for HLM and rCYP3A4. Pharmacokinetic parameters in Sprague-Dawley rats showed that apatinib caused significant increases in AUC_(0-t), AUC_(0-∞), C_max, T_max and t_1/2, while a significant decrease in CL_z/F for albendazole. For the metabolites albendazole sulfoxide and hydroxyalbendazole, apatinib caused significant increases in AUC_(0-t), AUC_(0-∞), and T_max, while a significant decrease in CL_z/F. In summary, apatinib could inhibit the metabolism of albendazole in vitro and in vivo, so albendazole should be closely monitored for adverse effects when used in combination with apatinib and discontinued if necessary.