We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.

我们研究了抗甲状腺癌药物凡德他尼在大鼠动物模型中的体外代谢，并证明N-去甲基凡德他尼和凡德他尼N-氧化物是由大鼠肝微粒体和纯生物转化酶催化的 NADPH 或 NADH 介导的反应形成的。 . 除了 vandetanib 代谢物的结构特征外，还鉴定了能够氧化 vandetanib 的单个大鼠酶 [细胞色素 P450 (CYP) 和含黄素的单加氧酶 (FMO)]。CYP3A 和 2C 抑制剂减弱了N-去甲基vandetanib的产生，但不是 vandetanib N-氧化物的产生，而 FMO 的抑制减少了 vandetanib N的形成-氧化物。这些结果表明，肝微粒体 CYP2C/3A 和 FMO1 分别是参与N-去甲基凡德他尼和凡德他尼N-氧化物形成的主要酶。大鼠重组CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2可有效催化N-去甲基万德他尼的形成。本研究的结果解释了先前报道的大鼠和人肝脏中 CYP 和 FMO 催化的凡德他尼氧化之间的差异以及该现象背后的酶学机制。