UHPLC–Q-TOF–MS/MS-based metabolite profiling of duvelisib and establishment of its metabolism mechanisms

Duvelisib is a dual inhibitor of phosphoinositide 3 kinase that received global approval by the US Food and Drug Administration in 2018 to treat follicular lymphoma after at least two prior systemic therapies. An extensive literature search revealed that, to date, metabolites of duvelisib have not been characterized and information on them is not available in any of the literature. Moreover, the metabolism pathway is yet to be established. This study aimed to investigate and characterize the metabolites of duvelisib generated in microsomes and S9 fractions. In this study, five duvelisib metabolites were identified using UHPLC–Q-TOF–MS/MS analysis technique. The structural characterization of the metabolites was performed by comparing the fragmentation pattern of duvelisib and its metabolites through an accurate mass measurement technique. Three metabolites were generated through phase I hydroxylation and dechlorination reactions. The other two metabolites were generated through a phase II glucuronidation reaction. The metabolism mechanism established through this study can be useful to improve the safety profile of drugs of similar categories in the future after establishment of the toxicity profile of the identified metabolites.