TY - JOUR
T1 - Metalloporphyrin-Catalyzed Oxidation of Sunitinib and Pazopanib, Two Anticancer Tyrosine Kinase Inhibitors:
T2 - Evidence for New Potentially Toxic Metabolites
AU - Paludetto, M. N.
AU - Bijani, C.
AU - Puisset, F.
AU - Bernardes-Génisson, V.
AU - Arellano, C.
AU - Robert, A.
PY - 2018
Y1 - 2018
N2 - Oxidation of two tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib, using a chemical catalytic system able to mimic the cytochrome P450 type oxidation, allowed us to prepare putative reactive/toxic metabolites of these anticancer drugs. Among these metabolites, aromatic aldehyde derivatives were unambiguously characterized. Such biomimetic oxidation of TKI-type drugs was essential to facilitate the identification of low amounts of aldehydes generated from these TKIs when incubated with human liver microsomes (HLM), which are classical models of human hepatic metabolism. These TKI derivative aldehydes quickly react in vitro with amines. A similar reaction is expected to occur in vivo and may be at the origin of the potentially severe hepatotoxicity of these TKIs.
AB - Oxidation of two tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib, using a chemical catalytic system able to mimic the cytochrome P450 type oxidation, allowed us to prepare putative reactive/toxic metabolites of these anticancer drugs. Among these metabolites, aromatic aldehyde derivatives were unambiguously characterized. Such biomimetic oxidation of TKI-type drugs was essential to facilitate the identification of low amounts of aldehydes generated from these TKIs when incubated with human liver microsomes (HLM), which are classical models of human hepatic metabolism. These TKI derivative aldehydes quickly react in vitro with amines. A similar reaction is expected to occur in vivo and may be at the origin of the potentially severe hepatotoxicity of these TKIs.
UR - https://www.ncbi.nlm.nih.gov/pubmed/30102538
U2 - 10.1021/acs.jmedchem.8b00812
DO - 10.1021/acs.jmedchem.8b00812
M3 - Article
SN - 0022-2623
VL - 61
SP - 7849
EP - 7860
JO - J Med Chem
JF - J Med Chem
IS - 17
ER -