AbstractPiperlongumine (PPL), a natural plant product, has been extensively studied in cancer treatment going up on clinical trials. Since the first report related to its use on cancer research (in 2011) around 80 papers have been published in less than 10 years, but a gap still remaining. There are no metabolism studies of PPL in human organism. For the lack of a better view, here, the CYP450in vitrooxidation of PPL was described for the first time. In addition, the enzymatic kinetic data, the predictedin vivoparameters, the produced metabolites, the phenotyping study and possible piperlongumine-drug interactionsin vivois presented.