Metabolism profiling of amino-noscapine

Abstract

Amino-noscapine is a promising noscapine derivative undergoing R&D as an efficient anti-tumor drug. In vitro phase I metabolism incubation system was employed. In vitro samples were analyzed using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. In vitro recombinant CYP isoforms screening was used to identify the drug-metabolizing enzymes involved in the metabolism of amino-noscapine. Multiple metabolics were formed, including the formation of metabolite undergoing cleavage of methylenedioxy group, hydroxylated metabolites, demethylated metabolites, and metabolites undergoing C-C cleavage. Nearly, all the CYP isoforms were involved in the metabolism of metabolites II, III, VII, IX, and X. CYP1A1 was demonstrated to be the major CYP isoform for the formation of metabolites IV and V. CYP1A1 and CYP3A4 mainly catalyzed the formation of metabolite VI. The metabolic formation of VIII was mainly catalyzed by CYP2C19 and CYP3A4. CYP3A4 was the main enzyme for the formation of XI. CYP2C9 mainly catalyzed the generation of metabolite XII. In conclusion, the metabolic pathway of amino-noscapine was elucidated in the present study using in vitro phase I incubation experiment, including the structural elucidation of metabolites and involved phase I drug-metabolizing enzymes. This information was helpful for the R&D of amino-noscapine.