title: Characterization of the in vivo and in vitro metabolic profile of PAC-1 using liquid chromatography-mass spectrometry.
abstract: In the present study, the metabolic profile of PAC-1, a potential anticancer drug, was investigated using liquid chromatography-mass spectrometric (LC/MS) techniques. Two different types of mass spectrometers--a quadrupole time-of-flight (Q-TOF) mass spectrometer and an ion trap (IT) mass spectrometer--were employed to acquire structural information on PAC-1 metabolites. A gradient liquid chromatographic system composed of 0.2% formic acid in methanol and 0.2% formic acid in water was used for metabolite separation on an Agilent TC-C(18) column. A total of 16 metabolites were detected. The corresponding product ion spectra were acquired and interpreted, and structures were proposed. Accurate mass measurement using LC-Q-TOF was used to determine the elemental composition of metabolites thereby confirming the proposed structures of these metabolites. Phase I metabolic changes were predominantly observed, including debenzylation, dihydrodiol formation, hydroxylation, and dihydroxylation. The detected phase II metabolites included PAC-1 and hydroxylated PAC-1 glucuronide conjugates. Based on metabolite analysis, several PAC-1 metabolic pathways in rat were proposed.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ren
authors.forename: Kaishun
authors.initials: K
authors.lastname: Bi
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.forename: Weiming
authors.initials: W
authors.lastname: Cheng
authors.forename: Zhen
authors.initials: Z
authors.lastname: Song
authors.forename: Lina
authors.initials: L
authors.lastname: Fang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D005243:Feces / Q000737:chemistry; D006835:Hydrazones / Q000378:metabolism*; D008297:Male; D055442:Metabolome; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D000970:Antineoplastic Agents; D006835:Hydrazones; D010879:Piperazines