title: Identification of metabolites of the novel anti-tumor drug candidate MDH-7 in rat urine by liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry.
abstract: BACKGROUND
  Our previous preliminary pharmacokinetic study demonstrated that the novel double pyrimidine tricyclic nucleoside MDH-7 in rats had a very short half-life (<30 min) after oral administration. As a result, the in vivo metabolic profile of MDH-7 should be investigated during early stages of drug development to better select drug candidates.
  
  
  METHODS
  In this study, a rapid method was developed to identify the metabolites of MDH-7 in rat urine by means of ultra-performance liquid chromatography (UPLC) coupled with electrospray ionization mass spectrometry (ESI-MS) using a triple quadrupole linear ion trap instrument. MDH-7 and its metabolites were detected and characterized by the combined use of the multiple reaction monitoring-information-dependent acquisition-enhanced product ion (MRM-IDA-EPI) mode and the precursor scan information-dependent acquisition-enhanced product ion (PREC-IDA-EPI) mode.
  
  
  RESULTS
  Ten novel metabolites of MDH-7 were identified and characterized in rat urine by LC/ESI-MS and collision-induced dissociation tandem mass spectrometry (CID-MS/MS) analyses. M1 was identified as 5-fluoro-N(4) -[(pentyloxy)carbonyl]cytosine; M2 and M3 were formed by hydroxylation products of M1. Metabolites M4-M10 were formed by a series of degradation reactions such as: deacetylation, hydroxylation, loss of the defluorocytosine base, oxidative-deamination, loss of the defluorouracil base, N-dealkylation and amide hydrolysis.
  
  
  CONCLUSIONS
  Based on the profiles of the metabolites, possible metabolic pathways of MDH-7 in rats were proposed for the first time. This study provides new and available information on the metabolism of MDH-7 which is very useful to further understand its in vivo metabolic fate. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.|Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou, 450001, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Diao
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Yingqian
authors.initials: Y
authors.lastname: Su
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Qingli
authors.initials: Q
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Zhicun
authors.initials: Z
authors.lastname: Yao
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Yi
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Jin
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Mengru
authors.initials: M
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.|Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou, 450001, China.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine*; D002853:Chromatography, Liquid / Q000379:methods*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents