Find in Library

The metabolism of vandetanib, a tyrosine kinase inhibitor used for treatment of symptomatic/progressive medullary thyroid cancer, was studied using human hepatic microsomes, recombinant cytochromes P450 (CYPs) and flavin-containing monooxygenases (FMOs). The role of CYPs and FMOs in the microsomal metabolism of vandetanib to <i>N</i>-desmethylvandetanib and vandetanib-<i>N</i>-oxide was investigated by examining the effects of CYP/FMO inhibitors and by correlating CYP-/FMO-catalytic activities in each microsomal sample with the amounts of <i>N</i>-desmethylvandetanib/vandetanib-<i>N</i>-oxide formed by these samples. CYP3A4/FMO-activities significantly correlated with the formation of <i>N</i>-desmethylvandetanib/ vandetanib-<i>N</i>-oxide. Based on these studies, most of the vandetanib metabolism was attributed to <i>N</i>-desmethylvandetanib/vandetanib-<i>N</i>-oxide to CYP3A4/FMO3. Recombinant CYP3A4 was most efficient to form <i>N</i>-desmethylvandetanib, while FMO1/FMO3 generated <i>N</i>-oxide. Cytochrome b₅ stimulated the CYP3A4-catalyzed formation of <i>N</i>-desmethylvandetanib, which is of great importance because CYP3A4 is not only most efficient in generating <i>N</i>-desmethylvandetanib, but also most significant due to its high expression in human liver. Molecular modeling indicated that binding of more than one molecule of vandetanib into the CYP3A4-active center can be responsible for the high efficiency of CYP3A4 <i>N</i>-demethylating vandetanib. Indeed, the CYP3A4-mediated reaction exhibits kinetics of positive cooperativity and this corresponded to the in silico model, where two vandetanib molecules were found in CYP3A4-active center.