Identification and characterization of in vitro phase I and reactive metabolites of masitinib using a LC-MS/MS method: bioactivation pathway elucidation

Abstract

In vitro phase I metabolic reactions & cyano conjugates of masitinib.

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

“…Iminium carbonyl intermediates were also observed after subsequent piperazine oxidation. Similar metabolic activation pathways on the piperazine ring were reported for imatinib 26 in HLM and for entrectinib 10 , masitinib 76 , and ponatinib 68 in RLM (Figure ).…”

“…Filppula et al showed in vitro in HLM incubations that masitinib is not a CYP3A4 nor a CYP2C8 time‐dependent inhibitor. Iminium and iminium carbonyl RM 78 arising from piperazine bioactivation have recently been evidenced since cyanide adducts 79 have been detected in vitro (Figure ). It is interesting to note that, contrary to the structurally related TKI imatinib, an imine‐methide RM has not been evidenced in GSH trapping experiments in this study, though hydroxylation on the methyl group of the toluidine ring has been observed.…”

Reactive intermediates in copanlisib metabolism identified by LC-MS/MS: phase I metabolic profiling

“…bioactivation have been previously studied in cyclic tertiary amine-containing drugs. [33][34][35][36][37][38] The formation of M439 and M512 conrmed the production of aldehyde intermediates in CNB metabolism. The aldehyde electrophiles were formed by oxidative dealkylation Scheme 1 Proposed mechanism for the formation of iminium intermediates in CNB metabolism and the potential trapping strategy.…”

LC-MS/MS reveals the formation of aldehydes and iminium reactive intermediates in foretinib metabolism: phase I metabolic profiling

“…Centrifugation for the incubation mixture (14 000 rpm, 10 min and 4 C) was done to devoid of proteins. The supernatants were removed, evaporated and reconstituted in ACN/ water and transferred to HPLC vial to be injected into Agilent 6410 LC-MS. 21,22 2.4. Trapping foretinib reactive metabolites using methoxylamine and potassium cyanide…”

“…The pathway of formation of iminium intermediate and foretinib bioactivation is previously described with cyclic tertiary amine containing drugs. 21,22 The formation of FM591 and FM607 indicated that their aldehyde intermediates were generated in the metabolism of foretinib. The aldehyde (FM591) was generated by dealkylation and trapped with methoxylamine to form oxime FM607 was produced in two steps.…”