Daporinad in vitro metabolite profiling via rat, dog, monkey and human liver microsomes by liquid chromatography/quadrupole‐orbitrap mass spectrometry

Rationale Daporinad is a novel and potent inhibitor of nicotinamide phosphoribosyl transferase with potential antineoplastic and antiangiogenic activities. We aimed to explore the metabolites of daporinad generated from liver microsomes and to propose metabolic pathways. Methods The metabolites were generated by individually incubating daporinad (10 μM) with liver microsomes at 37°C for 60 min. The metabolites were identified by ultra‐high‐performance liquid chromatography/quadrupole‐orbitrap mass spectrometry (UPLC/Q‐Orbitrap‐MS) using electrospray ionization in positive ion mode. They were deduced by accurate MS and MS/MS data. Results In total, 16 metabolites were found and their identities were characterized. In rat, dog and human, they were minor; in monkey, M11 was the most abundant. Daporinad was metabolized mainly through N‐dealkylation, amide hydrolysis, hydrogenation, oxygenation and dehydrogenation. There was no human‐specific metabolite. Conclusions The current study provided an overview of the metabolism of daporinad, which is helpful in predicting in vivo metabolites and in selecting animal species for toxicology studies.