Abstract
Ponatinib (Iclusig®) is a multi-targeted tyrosine kinase inhibitor (TKIs). It is active against T315I and other BCR-ABL mutants. Investigation of in vivo metabolism of ponatinib was done using Sprague Dawley rats by giving one oral dose of PNT (4.7 mg/kg) to each rat and urine samples were gathered at several time intervals from dosing. Filteration of urine samples was done through 0.45 μm syringe filters. Phase separation using ACN was applied for extraction of ponatinib related metabolites. Characterization and identification of one in vivo phase II metabolite and thirteen in vivo phase I of PNT were done using LC-MS/MS. Phase I metabolic reactions were reduction, N-demethylation, hydroxylation, N-oxidation, oxidation and amide hydrolysis. Phase II metabolic reaction was glucuronidation of hydroxyl benzyl metabolites of ponatinib. The major in vivo metabolic reactions were α hydroxylation and α oxidation at piperazine ring. Literature review revealed no articles that have been published on in vivo metabolism of ponatinib in Sprague Dawley rats or ponatinib in vivo phase I and phase II metabolites structural characterization and identification.
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•Thirteen in vivo phase I and one in vivo phase II metabolites of ponatinib were characterized in rat urine by LC-MS/MS.•Phase separation between an aqueous sample and ACN was used for extraction of ponatinib metabolites.•The major in vivo metabolic reactions were α hydroxylation and α oxidation at the N-methyl piperazine ring.•Oxidized cyclic tertiary amines can be the main reason for ponatinib toxicity due to reactive electrophiles formation.