Environmental Toxicology and Pharmacology ( IF 3.292 ) Pub Date : 2019-12-03 , DOI: 10.1016/j.etap.2019.103310 Radek Indra,Petr Pompach,Katarína Vavrová,Kateřina Jáklová,Zbyněk Heger,Vojtěch Adam,Tomáš Eckschlager,Kateřina Kopečková,Volker Manfred Arlt,Marie Stiborová
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.