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 N-desmethylvandetanib and vandetanib-N-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 N-desmethylvandetanib/vandetanib-N-oxide formed by these samples. CYP3A4/FMO-activities significantly correlated with the formation of N-desmethylvandetanib/ vandetanib-N-oxide. Based on these studies, most of the vandetanib metabolism was attributed to N-desmethylvandetanib/vandetanib-N-oxide to CYP3A4/FMO3. Recombinant CYP3A4 was most efficient to form N-desmethylvandetanib, while FMO1/FMO3 generated N-oxide. Cytochrome b5 stimulated the CYP3A4-catalyzed formation of N-desmethylvandetanib, which is of great importance because CYP3A4 is not only most efficient in generating N-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 N-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.

• Keywords
• cytochromes P450, flavin-containing monoxygenases, metabolism, tyrosine kinase inhibitor, vandetanib,
• MeSH
• Quinazolines chemistry   pharmacology   MeSH
• Cytochrome P-450 CYP3A chemistry   metabolism   MeSH
• Enzymes chemistry   metabolism   MeSH
• Protein Kinase Inhibitors chemistry   pharmacology   MeSH
• Microsomes, Liver metabolism   MeSH
• Rabbits MeSH
• Rats MeSH
• Humans MeSH
• Molecular Conformation MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Mice MeSH
• Oxidation-Reduction * MeSH
• Piperidines chemistry   pharmacology   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Recombinant Proteins MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Rats MeSH
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Quinazolines MeSH
• Cytochrome P-450 CYP3A MeSH
• Enzymes MeSH
• Protein Kinase Inhibitors MeSH
• Piperidines MeSH
• Antineoplastic Agents MeSH
• Recombinant Proteins MeSH
• vandetanib MeSH Browser